Diagnostic procedures using direct injection of gaseous hyperpolarized 129xe and associated systems and products

ABSTRACT

A method of screening for pulmonary embolism uses gaseous phase polarized  129 Xe which is injected directly into the vasculature of a subject. The gaseous  129 Xe can be delivered in a controlled manner such that the gas substantially dissolves into the vasculature proximate to the injection site. Alternatively, the gas can be injected such that it remains as a gas in the bloodstream for a period of time (such as about  8 - 29  seconds). The injectable formulation of polarized  129 Xe gas is presented in small quantities of (preferably isotopically enriched) hyperpolarized  129 Xe and can provide high-quality vasculature MRI images or NMR spectroscopic signals with clinically useful signal resolution or intensity. One method injects the polarized  129 Xe as a gas into a vein and also directs another quantity of polarized gas into the subject via inhalation. In this embodiment, the perfusion uptake allows arterial signal information and the injection (venous side) allows venous signal information. The dual delivery is used to generate a combined introduction path with a more complete image signal of both the arterial and venous side of the pulmonary vasculature. In this NMR imaging method, the pulmonary embolism screening method can use the same NMR chest coil for the excitation and detection of the  129 Xe signals. The direct injection of small quantities of gas at particular sites along the vasculature targets specific target regions to provide increased signal intensity NMR images. The disclosure also includes related methods directed to other diagnostic vasculature regions physiological and conditions. Associated delivery and dispensing systems and methods, containers, and quantitative formulations of the polarized gas are also described.

RELATED APPLICATIONS

This application claims the benefit of priority from U.S. ProvisionalApplication Ser. No. 60/189,072 filed Mar. 13, 2000, the contents ofwhich are hereby incorporated by reference as if recited in full herein.

FIELD OF THE INVENTION

The present invention relates generally to magnetic resonance imaging(“MRI”) and spectroscopy methods, and more particularly to the use ofhyperpolarized ¹²⁹Xe in MRI and spectroscopy.

BACKGROUND OF THE INVENTION

MRU using hyperpolarized noble gases has been demonstrated as a viableimaging modality. See e.g., U.S. Pat. No. 5,545,396 to Albert et al. Thecontents of this patent are hereby incorporated by reference as ifrecited in full herein. Albert et al. proposed several techniques ofintroducing the hyperpolarized gas (either alone or in combination withanother substance) to a subject, such as via direct injection,intravenous injection, and inhalation. See also Biological magneticresonance imaging using laser-polarized ¹²⁹Xe, 370 Nature, pp. 199-201(Jul. 21, 1994). Other researchers have since obtained relativelyhigh-quality images of the lung using pulmonary ventilation of the lungwith both hyperpolarized ³He and ¹²⁹Xe. See J. R. MacFall, H. C.Charles, R. D. Black, H. Middleton, J. Swartz, B. Saam, B. Driehuys, C.Erickson, W. Happer, G. Cates, G. A. Johnson, and C. E. Ravin, “Humanlung air spaces: Potential for MR imaging with hyperpolarized He-3,”Radiology 200, 553-558 (1996); and Mugler et al., MR Imaging andspectroscopy using hyperpolarized 129Xe gas: Preliminary human results,37 Mag. Res. Med., pp. 809-815 (1997). See also E. E. de Lange, J. P.Mugler, J. R. Brookeman, J. Knight-Scott, J. Truwit, C. D. Teates, T. M.Daniel, P. L. Bogorad, and G. D. Cates, “Lung Airspaces: MR ImagingEvaluation with Hyperpolarized Helium-3 Gas,” Radiology 210, 851-857(1999); L. F. Dormelly, J. R. MacFall, H. P. McAdams, J. M. Majure, J.Smith, D. P. Frush, P. Bogorad, H. C. Charles, and C. E. Ravin, “CysticFibrosis: Combined Hyperpolarized 3He-enhanced and Conventional ProtonMR Imaging in the Lung—Preliminary Observations,” Radiology 212(September 1999), 885-889 (1999); H. P. McAdams, S. M. Palmer, L. F.Donnelly, H. C. Charles, V. F. Tapson, and J. R. MacFall,“Hyperpolarized 3He-Enhanced MR Imaging of Lung Transplant Recipients:Preliminary Results,” AJR 173, 955-959 (1999).

In addition, due to the high solubility of ¹²⁹Xe in blood and tissues,vascular and tissue imaging using inhaled hyperpolarized ¹²⁹Xe has alsobeen proposed. Generally described, during inhalation delivery, aquantity of hyperpolarized ¹²⁹Xe is inhaled by a subject (a subjectbreathes in the ¹²⁹Xe gas) and the subject then holds his or her breathfor a short period of time, i.e., a “breath-hold” delivery. This inhaled¹²⁹Xe gas volume then exits the lung space and is generally taken up bythe pulmonary vessels and associated blood or pulmonary vasculature at arate of approximately 0.3% per second. For example, for an inhaledquantity of about 1 liter of hyperpolarized ¹²⁹Xe, an estimated uptakeis about 3 cubic centimeters per second or a total quantity of about 40cubic centimeters of ¹²⁹Xe over about a 15 second breath-hold period.Accordingly, it has been noted that such uptake can be used to generateimages of pulmonary vasculature or even organ systems more distant fromthe lungs. See co-pending and co-assigned U.S. patent application Ser.No. 09/271,476 to Driehuys et al, entitled Methods for Imaging Pulmonaryand Cardiac Vasculature and Evaluating Blood Flow Using DissolvedPolarized ¹²⁹Xe. Although primarily directed to inhalation delivery,this application also proposes injection of ¹²⁹Xe to replaceconventional radioactive tracers in perfusion imaging methods. Thecontents of this application are hereby incorporated by reference as ifrecited in full herein.

Many researchers are also interested in the possibility of using inhaled¹²⁹Xe for imaging white matter perfusion in the brain, renal perfusion,and the like. While the inhaled delivery ¹²⁹Xe methods are suitable, andindeed, preferable, for many MRI applications for several reasons, suchas the non-invasive characteristics attendant with such a delivery to ahuman subject, it may not be the most efficient method to deliver asufficiently large dose to more distant (away from the pulmonaryvasculature which is proximate to the lungs) target areas of interest.In addition, due to the dilution of the inhaled ¹²⁹Xe along theperfusion delivery path, relatively large quantities of thehyperpolarized ¹²⁹Xe are typically inhaled in order to deliver a smallfraction of the gas to the more distal target sites or organ systems.For example, the brain typically receives only about 13% of the totalblood flow in the human body. Thus, the estimated 40 cubic centimeterquantity of hyperpolarized ¹²⁹Xe taken up into the pulmonary vesselsfrom the 1-liter inhalation dose can be reduced to only about 5 cubiccentimeters by the time it reaches the brain.

Further, the hyperpolarized state of the gas is sensitive and can decayrelatively quickly due to a number of relaxation mechanisms. Indeed, therelaxation time (generally represented by a decay constant “T₁”) of the¹²⁹Xe in the blood, absent other external depolarizing factors, isestimated at T₁=4.0 seconds for venous blood and T₁=6.4 s for arterialblood at a magnetic field strength of about 1.5 Tesla. See Wolber etal., Spin-lattice relaxation of laser-polarized xenon in human blood, 96Proc. Natl. Acad. Sci. USA, pp. 3664-3669 (March 1999). (The moreoxygenated arterial blood provides increased polarization life over therelatively de-oxygenated venous blood). Therefore, for about a 5 secondtransit time (the time estimate for the uptaken hyperpolarized ¹²⁹Xe totravel to the brain from the pulmonary vessels), the ¹²⁹Xe polarizationis reduced to about 37% of its original value. In addition, therelaxation time of the polarized ¹²⁹Xe in the lung itself is typicallyabout 20-25 seconds due to the presence of paramagnetic oxygen.Accordingly, ¹²⁹Xe taken up in the latter portion of the breath-holdcycle can decay to have only about 50% of the starting polarization (thepolarization level at the initial portion of the breath hold cycle).Thus, generally stated, the average polarization of ¹²⁹Xe entering thepulmonary blood can be estimated to be at about 75% of the startinginhaled polarization value. Taking these effects into account, thedelivery to the brain of the inhaled ¹²⁹Xe can be estimated as about 1.4cubic centimeters of the inhaled one-liter dose of ¹²⁹Xe polarized tothe same level as the inhaled gas (0.75×0.37×5 cc's). This dilutionreduces delivery efficiency, i.e., for remote target areas (such as thebrain), the quantity of delivered ¹²⁹Xe is typically severely reduced toonly about 0.14% of the inhaled ¹²⁹Xe. Nonetheless, at least oneresearcher has made coarse images of ¹²⁹Xe in rat brains, but thisinhalation administration delivery required large quantities of ¹²⁹Xe tobe inhaled over a relatively long period of time. See Swanson et al.,Brain MRI with laser-polarized xenon in human blood, 38 Mag. Reson.Med., pp. 695-698 (1997). Unfortunately, the extended inhalation timeperiod and/or associated large quantity dosage of the gas may not bedesirable for certain clinical applications.

In an alternative delivery mode, Bifone et al. proposes the use ofinjectable formulations to deliver hyperpolarized ¹²⁹ Xe to regions ofinterest. Bifone et al., NMR of laser polarized xenon in human blood, 93Proc. Natl. Acad. Sci. USA No. 23, pp. 12932-12936 (1996). Albert etal., supra, also describes such formulations. As described by Bifone etal., the injectable formulation consists of a biocompatible fluid inwhich hyperpolarized ¹²⁹Xe is dissolved. Such formulations can then beinjected intravenously to deliver hyperpolarized ¹²⁹Xe. For fluidinjection, the formulation is described as preferably formed such thatthe biocompatible fluid has a high solubility for xenon while alsoproviding a relatively long ¹²⁹Xe relaxation time. Examples ofparticular suggested biocompatible fluids include saline, lipidemulsions, and perfluorocarbon emulsions. Several researchers have shownimages of fluid injectable formulations. For example, Goodson et al.have shown images of ¹²⁹Xe dissolved in saline and injected into thehind leg of a rat. Goodson et al., In vivo NMR and MRI Using InjectionDelivery of Laser-Polarized Xenon, 94 Proc. Natl. Acad. Sci. USA, pp.14725-14729 (1997). Moeller et al. have also recently demonstratedvenous angiography with hyperpolarized ¹²⁹Xe dissolved in Intralipid®solution. Moeller et. al., Magnetic Resonance Angiography withHyperpolarized ¹²⁹ Xe Dissolved in Lipid Emulsion, 41 Mag. Res. Med. No.5, pp. 1058-1064 (1999). The Intralipid® formulation purportedly has axenon-Otswald solubility of about 0.6 and a ¹²⁹Xe relaxation time of 25seconds in a magnetic field strength of 2.0 Tesla. In addition, Wolberet al, have also recently demonstrated PFOB (perfluorooctyl bromide)emulsions which allegedly have increased transverse relaxation times andhave purportedly provided improved imaging results. Wolber et al.,Perfluorocarbon Emulsions as Intravenous Delivery Media forHyperpolarized Xenon, 41 Mag. Res. Med., pp. 442-449 (1999). In yetanother injection technique, Chawla et al., have proposed the use ofhyperpolarized ³He microbubbles suspended in a hexabrix solution toperform angiography on rats. Chawla et al., In Vivo Magnetic ResonanceVascular Imaging Using Laser-Polarized 3He Microbubbles, 95 Proc. Natl.Acad. Sci. USA, pp. 10832-10835 (1998).

Unfortunately, many injectable formulations can be unduly susceptible tohandling and processing variables which can negatively impact theinjectable formulation's commercial viability and/or clinicalapplication. For example, the relatively short (and potentiallymagnetic-field dependent) relaxation time of the ¹²⁹Xe in the injectablesolutions can require that the ¹²⁹Xe gas be dissolved into thebiocompatible fluid relatively quickly and then subsequently rapidlyinjected to reduce the polarization loss of the formulation prior toinjection. In addition, it may be difficult to predict the dissolutionefficiency in a manner which can provide a reliable xenon dissolutionconcentration. Unreliable concentrations can, unfortunately, yieldwidely varying signal intensities, dose to dose. Further, because of thetypically relatively quick decay associated with these formulations, acareful measurement of the final ¹²⁹Xe polarization just prior toinjection to determine the post dissolution polarization may not bepossible. Still further, because the ¹²⁹Xe is dissolved in abiocompatible fluid, sensitivity to the local in vivo environment suchas blood oxygenation, tissue type, and the like, may be muted, reduced,or even non-existent. The use of such fluids or carrier agents todeliver ¹²⁹Xe to selected tissues or organs can also be difficultbecause of the high solubility of ¹²⁹Xe in the fluid compared to thetissues (its preferred affinity being to remain in the fluid rather thanto migrate into the selected or targeted tissues).

In view of the foregoing, and despite the present efforts, therecontinues to be a need to improve the methods, products, and systemsused to deliver hyperpolarized ¹²⁹Xe gas to a target in vivo imagingregion of interest.

OBJECTS AND SUMMARY OF THE INVENTION

It is therefore an object of the present invention to formulate anddeliver ¹²⁹Xe in vivo in a manner which allows for high-qualitymammalian tissue, organ, vascular, and/or angiographic MRI images usinghyperpolarized gaseous ¹²⁹Xe.

It is another object of the present invention to provide a method ofusing reduced quantities of hyperpolarized gas while providing increasedMRI image signal resolution.

It is an additional object of the present invention to provide methodsfor obtaining improved quality NMR signals and/or MRI images of both thearterial and venous portions of the human vasculature and/or organsand/or systems using hyperpolarized ¹²⁹Xe.

It is a further object of the present invention to provide appropriate(bolus) sized containers and associated delivery systems, apparatus, andmethods which can reduce the depolarization of the hyperpolarized ¹²⁹Xegas prior to and during delivery and can, thus, yield a clinicallyuseful T₁.

It is another object of the present invention to introduce a sufficientquantity of hyperpolarized ¹²⁹Xe gas into the vasculature in a minimallyintrusive manner to obtain MR spectroscopic signal and/or in vivoimages.

It is yet another object of the present invention to facilitate thedissipation or dispersion of bubbles which may be injected into asubject.

It is an additional object of the present invention to provide imagingmethods which may be able to screen for the presence of pulmonaryemboli.

It is still another object of the invention to formulate ¹²⁹Xe as apharmaceutical grade injectable formulation which can be monitored forpolarization efficacy just prior to use with reduced decaying effectthereon.

It is another object of the present invention to provide NMR-baseddiagnostic capability of vasculature (arterial and/or venous or organ)circulation related defects or emboli in a minimally or non-invasive andeffective manner.

It is yet another object of the present invention to provide adiagnostic tool for the evaluation of pharmaceutical effectiveness ondrugs directed to target regions or functions.

It is an additional object of the present invention to provide in vivodiagnostic information regarding the cancerous condition of a solidmass.

It is another object of the present invention to prepare gas contactingsurfaces and containers in a manner which reduces the amount ofdepolarizing oxygen therein while also employing purge gas which issuitable for injection.

It is still an additional object of the present invention to provide away to optimize capillary length for improved polarization life incontainers configured to hold polarized noble gases such as ¹²⁹Xe and/or³He.

These and other objects of the present invention are provided bydirectly injecting in vivo a predetermined quantity of hyperpolarized¹²⁹Xe in gaseous phase to obtain MR based spectroscopic signal or imagesregarding a target site in the mammalian vasculature (or target organ,tissue, or region). The present invention also includes delivery anddispensing methods, systems, and product formulations, as well asadministration rates which may correspond to the use or injection site.In addition, the present invention provides polarization monitoring ofthe hyperpolarized gaseous ¹²⁹Xe which is formulated for directinjection in vivo into the vasculature for MR imaging and spectroscopicanalysis.

In particular, a first aspect of the present invention is directedtoward the detection or screening for the presence of a pulmonaryembolism. The method includes the step of positioning a subject having apulmonary region and a blood circulation path including veins andarteries in a NMR system. The subject's pulmonary region has pulmonaryveins and pulmonary arteries and associated vasculature defining apulmonary portion of the circulation path. A quantity of polarizedgaseous ¹²⁹Xe is injected directly into at least one vein of thesubject. NMR signal data associated with the polarized ¹²⁹Xe in thepulmonary region of the subject is obtained. The signal data includesinformation corresponding to the polarized gas introduced in theinjecting step. An MRI image is generated having spatially coded visualrepresentation of the NMR signal data. The presence of at least onecondition of blockage, restriction, abnormality, and substantiallyunobstructed free passage of the pulmonary circulation path isidentified.

In one embodiment, the quantity of venous injected gaseous ¹²⁹Xe is lessthan about 100 cubic centimeters while quantity of arterial injectedgaseous ¹²⁹Xe is less than about 14-20 cc's.

In another embodiment, in order facilitate bubble dissipation which maybe associated with the injection of the ¹²⁹Xe gas within the subject, aquantity of liquid surfactant can be introduced in vivo temporally andspatially proximate to the gas injection (or concurrently at a locationproximate to the gas injection) site. The injection pressure and/or therate of injection can also be substantially controlled to therebycontrol the delivery rate of the polarized gaseous ¹²⁹Xe into theinjection site typically to about 1-3 cc/s or less for venous entry. Thegas injection may be performed in a manner which reduces the bubble sizeassociated with the injected gas to preferably to less than about 5-10μm in diameter for certain embodiments (particularly for arterialinjections) and less than about 75-150 μm in diameter for venousinjections.

In one embodiment, a second quantity of a polarized gas is introduced toa subject during the same imaging session. That is, the first quantityis injected and an associated first image or signal acquisition can beobtained, and a second delivery and a second data or signal acquisitionor image associated with the second quantity can be obtained. Forexample, the second delivery can be via inhalation of a hyperpolarizedgas (either ³He or ¹²⁹Xe, although for system equipment and coil tuningreasons, ¹²⁹Xe gas is preferred) and the signal/image can be obtainedafter a short lapsed time period from the first signal/image (a timesufficient to clear traces of the polarized injected xenon from thetarget area). Additionally, or alternatively, the inhalation dose can bedelivered prior to the injection of the polarized gas. Alternatively,concurrent delivery of the injection and inhalation doses may be used.It is anticipated that this may help with co-registration between thetwo images and may reduce image artifacts. Of course, the seconddelivery can be another injectable dose of ¹²⁹Xe gas, or an injection ofa hyperpolarized gas product in liquid form (such as dissolved in acarrier liquid).

Another aspect of the present invention is directed toward a method ofobtaining MRI-based medical images. The method includes injectingdirectly into an injection site of a subject a first quantity ofpolarized ¹²⁹Xe in gaseous form and delivering a second quantity ofpolarized gas product to the subject within the same imaging session.The second delivery can be performed in a number of ways and with anumber of polarized noble gas product formulations. For example,inhalation of a polarized noble gas mixture (such as described for theembodiment above) or another injection (either of the ¹²⁹Xe gas directlyor of a polarized noble gas product otherwise formulated such as in acarrier or liquid based injection formulation) at a point in time whichis proximate to the injecting step. The second quantity is larger thanthe first (injected) quantity. An MRI image is then generatedcorresponding to the signal data acquisition obtained via NMR excitationof the first and second quantities of polarized gas introduced in saidinjecting and delivering steps.

In certain embodiments, the injecting step injection site is a siteassociated with the venous vasculature (such as a vein). In oneembodiment, the delivering step is carried out by administering twoseparate polarized gas based doses. That is, the delivery step may beperformed by injecting to second site in an artery and by inhaling aquantity of hyperpolarized gas. The second site or arterial injectionquantity can be in fluid or gas formulation. Thus, the inhalation baseddelivering step introduces the polarized gas via inhalation and theinhaled gas is subsequently directed into pulmonary arterial vasculaturevia perfusion uptake.

In another embodiment, the NMR signal data associated with both theinjecting and delivering steps is processed in a manner whichdistinguishes NMR signal information corresponding to gas versusdissolved gas signal information in the MRI image generating step.Alternatively, the MRI image-generating step is performed at a lowmagnetic field strength, and the NMR signal data is processed in amanner which combines or does not substantially distinguish between NMRsignal data associated with excitation of the hyperpolarized gas whetherin the gas phase or the dissolved phase (the peaks associated with thepolarized gas in the red blood cells and plasma in the blood overlap).

An additional aspect of the present invention is directed to a method ofobtaining diagnostic images of the cranial region. The method includesthe steps of injecting less than about 5 cc's (preferably about 1-2cc's) of ¹²⁹Xe polarized gas into an injection site in a carotid arteryand dissolving the polarized ¹²⁹Xe gas into the vasculature proximate tothe injection site. An NMR image is generated having signal intensityassociated with the NMR excitation of the dissolved ¹²⁹Xe. The signalcan be associated with the ¹²⁹Xe in one or more of the blood, greymatter, CSP, or white matter (to provide information corresponding towhite matter perfusion typical of desired neurological assessments). Theexcitation or response signal can be processed in a manner which allowsthe correlation to a particular region of interest, such as, forexample, highlighting differences in chemical shift, T₂*, T₁, and thelike as will be appreciated by one of skill in the art. The method caninclude, inter alia, the step of introducing, in vivo, a surfactant tofacilitate bubble dissipation proximate to the injection site

In one embodiment, the injecting step is performed at a (controlled)rate and/or pressure sufficient to facilitate the dissolution of the gasin the vasculature proximate to the injection site and/or in a mannerwhich reduces the size of bubbles introduced therewith corresponding tothe selected injection site (preferably to form smaller size bubbles andsmaller quantities of gas for arterial injections). An injection headwith multiple orifices sized with a diameter of between about 1 nm-50μm, and typically between about 0.01-10 μm can be used and the gas maybe mixed in situ with an emulsifier prior to delivery to facilitate afine dispersion of gas into the body of the subject.

Another aspect of the present invention is directed toward a method ofobtaining an MR image or NMR spectral data. The method includesinjecting less than about 100 cc's of hyperpolarized gas in vivo into aninjection site associated with the vasculature of a mammalian subject.An NMR image or spectral data is then generated corresponding to theinjected quantity of hyperpolarized ¹²⁹Xe gas.

In one embodiment the method includes the step of administering theinjection such that it remains substantially undissolved within thebloodstream for a period of time and such that it exhibits a T₁ in thebloodstream of at least eight seconds. Alternatively, the method canadminister the injection such that is employs an introduction rateselected so that the gas is dissolved (at least partially) into thevasculature proximate to the injection site and/or to reduce the size ofbubbles associated with the injection.

In certain embodiments, the injection is performed by injecting thehyperpolarized ¹²⁹Xe into at least one predetermined injection site suchas in an arm, leg, or at other externally accessible or viable injectionlocations. For example, the injection site can be chosen from the groupconsisting of a carotid artery, a pulmonary artery, a renal artery, ahepatic artery, and a renal artery or the group consisting of a veinlocated in the arm (such as the central vein or peripheral vein), ajugular vein, a pulmonary vein, a hepatic vein, and a renal vein. Inanother preferred embodiment, the injecting step is performed byinjecting the hyperpolarized ¹²⁹Xe into at least two different injectionsites, preferably the injection sites corresponding to a vein or arterywhich is externally accessible via injection of an IV or syringe needlesuch as in an arm, leg, or at other torso or other feasible locations.

The injection dose can be contained in a single-dose sized container.For arterial injections, the dose container can be sized and configuredto hold less than about 14-20 cc's of polarized ¹²⁹Xe gas therein. Forvenous injections, the dose container can be sized and configured tohold less than about 100 cc's of polarized ¹²⁹Xe gas therein. Thecontainer can be a syringe configured with a primary body with a wallhaving outer and inner surfaces, and the inner surface is formed from amaterial which reduces contact induced polarization decay associatedtherewith. Preferably, the syringe body is operably associated with acapillary stem and valve to control the exit of gas from the syringe.The syringe body can also include an NMR excitation coil mountedthereon. For delivery, it is preferred that a catheter is positioned ina subject at the desired injection site (corresponding to the desiredtarget image region in the subject). The catheter can include or beoperably associated with a frit or needle which is formed or coated witha polarization friendly material (such as a gold plated or aluminumneedle). The frit or needle may also be configured and sized to reducethe bubble size to at or below about a 10 micron diameter at injection.This reduced bubble size may be particularly suitable for arterialinjection sites.

In certain embodiments, an injection system for administering polarizedgas to a subject can include (a) a polarized noble gas supply; (b) acatheter configured and sized for intravenous or intrarterial placementin a subject in fluid communication with the supply of polarized noblegas; and (c) an injection head positioned in a distal portion of thecatheter. The injection head can comprise multiple orifices which areconfigured so that, in operation, hyperpolarized gas flows therethroughand out of the catheter into the subject. The orifices can be sized witha width which is between about 1 nm-50 μm, and typically between about0.01-10 μm.

In certain embodiments, the system can include an additive source (suchas an emulsifier source) and a mixing chamber positioned intermediatethe orifices and the additive or emulsifier and polarized gas sources tomix the hyperpolarized gas and the additive or emulsifier prior toexpulsion from the injector head orifices (typically it is mixed in situas the gas flows away from the gas source toward the exit orifice(s) inthe injection head). The system may also include a heating or coolingmeans to promote the generation of a fine dispersion of gas mixture fromthe injection head (which typically resides in an IV inserted into thebody).

In preparing the syringe, catheter, injection system, and/or conduitassociated therewith for use according to the present invention, CO₂ canbe employed as a purge gas to prepare the container and reduce thelikelihood of introducing nitrogen via injection into a subject(potentially leaving residual or traces of CO₂ rather than nitrogenwhich has been conventionally used to prepare the polarized gascontainers). As such, the injectable ¹²⁹Xe may include small quantitiesor traces of CO₂ therewith.

The system may include a resilient dose bag having external walls whichare responsive to the application of pressure thereagainst and aquantity of hyperpolarized gas held in the dose bag along with aninflatable bladder which is sized and configured to receive at least aportion of the dose bag therein. In operation, the inflatable bladder isinflated to press against the dose bag external walls to thereby expel aquantity of the hyperpolarized gas from the dose bag.

In one embodiment, the present invention is configured to employ a dualpath hyperpolarized gas product delivery system. For a manualpresentation and delivery, a technician can deliver the ¹²⁹Xe (inject)and then trigger a switch in the MRI unit indicating that the deliveryis complete. The MRI unit, in response to activation of the switch, caninitiate the imaging procedure such that it commences within therequired polarization life at the target-imaging region. The MRI unitcan also have a timer operably associated therewith which can alert thetechnician when it is acceptable to deliver the inhalation dose. Theinhalation dose can be an optional delivery which is withheld if noreasonable indicia of perfusion deficits are indicated by NMR signalobtained based on the injected dose. Of course, the injection dose andthe inhalation dose order can be reversed, wherein the injection dose isadministered second. In addition, automated delivery and sequencingmethods can also be employed as will be appreciated by one of skill inthe art.

For concurrent delivery, the system can include a user audible and/orvisual alert which is responsive to one or more of the dispensingsystems (it is activated when a gas or liquid polarized productcommences delivery at an IV or inhalation or other administration) thatallows the dispensing of more than one dose/path of gas (such as theinhaled and injected gas) to be timed or substantially concurrently (orat a predetermined or desired interval) administered. This canfacilitate the effective delivery and initiation of imaging sequenceswhich can be important due to the limited polarization life of thepolarized gas product in the blood.

An additional aspect of the present invention is a method of evaluatingthe efficacy of targeted drug therapy, comprising the steps ofdelivering a quantity of a predetermined gene treatment preparation orpharmaceutical drug in vivo into a mammalian subject having a targetsite and a treatment condition; injecting a predetermined quantity ofgaseous phase hyperpolarized ¹²⁹Xe in vivo into a mammalian subject suchthat the hyperpolarized gas is delivered to the target site in gaseousor dissolved form; generating a NMR image or spectroscopic signal of thetarget site associated with the injected hyperpolarized ¹²⁹Xe gas; andevaluating the NMR image or spectroscopic signal to evaluate theefficacy of the gene treatment or drug on the treatment conditionadministered in the delivering step.

In one embodiment, the method further comprises the step of acquiring atleast two sets of data, the data representing two temporally spacedapart points in time, to evaluate if the treatment condition isinfluenced by the drug or gene therapy introduced in the deliveringstep. Of course, the evaluation may be performed without regard totoxicity and/or survival if done in connection with animal research.

Another aspect of the invention is a method of determining the presenceof cancerous tissue, comprising the steps of delivering a quantity of apharmaceutical drug in vivo into a mammalian subject having a targetsite associated with a suspect mass or tissue abnormality; injecting aquantity of gaseous hyperpolarized ¹²⁹Xe in vivo into a mammaliansubject such that the hyperpolarized gas is delivered to the targetsite; generating a NMR image or spectroscopic signal of the target sitecorresponding to the injected hyperpolarized ¹²⁹Xe gas; and evaluatingthe NMR image or signal for the presence or absence of signaturepatterns in the generated image or signal associated with the presenceor absence of cancer.

An additional aspect of the present invention is an injectable ¹²⁹Xe gasproduct, the ¹²⁹Xe gas product formulated as a sterile non-toxichyperpolarized gas formulation which consists essentially ofisotopically enriched ¹²⁹Xe in gaseous phase which is injected in vivoin a quantity of less than about 20-100 cubic centimeters.

Similarly, another aspect of the present invention is an injectable¹²⁹Xe gas pharmaceutical grade product, the product formulated as asterile non-toxic product which consists essentially of ¹²⁹Xe in gaseousphase and traces of CO₂, wherein the injectable gas product isconfigured to be dispensed in vivo.

The present invention is advantageous because relatively smallquantities of (preferably isotopically enriched) hyperpolarized ¹²⁹Xegas with relatively predictable or known polarization levels can providehigh-quality MRI images or spectroscopy data with clinically usefulsignal resolution for in vivo tissue and/or vasculature. Indeed, in onepreferred embodiment, the pulmonary embolism detection method can beperformed as a relatively quick screening method typically with highquality diagnostic information about the circulatory path, such as inunder about 15 minutes. In this embodiment, it is preferred that both aninhalation (ventilation) and injection delivery of hyperpolarized gasare used to generate a combined (dual) introduction path. That is,inhalation can provide a first order image or ventilation image of thelungs. However, the gas migrates into the vasculature and/or is uptakenby the blood stream and, thus, is introduced into a pulmonary vein(s).This uptake can provide MRI or NMR venous spectra/information of thevenous side of the circulatory system. In contrast, the injection into avenous pathway can yield NMR arterial signal information (generallydescribed, the ¹²⁹Xe gas injected in a vein travels/flows to the rightside of the heart and then into a pulmonary artery). Therefore, the dualintroduction path can provide a more complete image/signal of both thearterial and venous side of the pulmonary vasculature. Conveniently, byusing polarized ¹²⁹Xe gas both as the inhalation and injection NMRmedium, the pulmonary embolism screening method can use the same NMRchest coil for the excitation and detection of the ¹²⁹Xe signalsassociated with the inhaled/perfusion dose and the injected dose.

Of course, direct injection of ¹²⁹Xe polarized gas to a particulartarget site such as a tumor can allow for additional diagnosticinformation over many conventional procedures. For example, in vivocancerous tumors can be characterized by the presence of increasedrandom blood vessel growth (a condition known as angiogenisis). This isin contrast to benign cysts. Taking advantage of this characteristic andthe NMR signal information available using direct ¹²⁹Xe polarized gasinjection, the present invention can analyze in vivo a target in anorgan such as a tumor in a breast. For example, a needle can be insertedor injected to the suspect region in the breast via conventional MRguided needle placement and ¹²⁹Xe can be released thereat (along with orin lieu of removing biopsy materials). Signature peaks in spectroscopysignals (or improved image resolution attributed to the hyperpolarized¹²⁹Xe signal) can indicate the presence of cancer via the increased peakin the signal due to the increased blood (and the injected xenon'ssolubility therewith). Of course, other contrast mechanisms likechemical shift, T₂*, diffusion, T₁, and the like, can also be employedto exploit the ¹²⁹Xe NMR image or spectroscopic signal in the tumor.

In addition, the present invention preferably employs a reliablequantitative concentration and/or predictable injection quantity. Thispredictable concentration of polarized gas can provide more predictableand reliable signal intensity for the associated MRI image, which, inturn, makes the method clinically useful as well as easier to correlate,patient to patient, or in a single patient over time. Preferably, theinjectable quantity is selected to correspond to the introduction(injection) site; the venous side can use increased quantities comparedto the arterial side (the venous side injections preferably sized atabout 100 cc's or less while the arterial injections are typically sizedat about 14-20 cc's or less.

In addition, the gas is preferably injected in a manner whichfacilitates reduced size bubbles introduced or formed by the injectingof gas. Controlling one or more of bubble size based on its responsiveparameters, the quantity of gas administered, and/or injection rate(release) (as well as the configuration of the nozzle or exit chamber)of the gas can assure that the gaseous delivery to vasculature is donein an effective manner.

In one embodiment, the in vivo introduction of a suitable surfactanttemporally and spatially proximate to (preferably upstream) the actualinjection of the gas (temporally before or concurrent to the gasinjection) can facilitate the dissipation or decreased size of injectedbubbles in the venous and/or arterial system (depending on the injectionsite).

Further, the present invention recognizes that in order to allow theinjected xenon gas sufficient time to enter the pulmonary vasculature,the NMR scanning is preferably delayed a sufficient amount of time afterinjection to allow for same, typically about 5-10 secondspost-injection. On the upper time limit, the NMR scan is also preferablyperformed within about one minute post-injection (and preferably 30seconds after injection) as the polarization level will decay to anundesirable level relatively shortly after introduction into the body.Of course, multiple serially successive quantities of administeredinjection doses can be administered during the imaging session forobtaining a plurality of sequential or multi-shot images.

The dispensing methods, containers, and other apparatus of the presentinvention are advantageously configured to facilitate a longer T₁ forthe polarized gas and, thus, to promote a single-bolus sized formulationwith a predictable level of polarization in a hyperpolarized product.Further, the ¹²⁹Xe injectable gas product can be delivered andformulated in a way which allows the gas to be analyzed to determine itspolarization level prior to delivery to thereby confirm the efficacy ofthe product just prior to (or in a preferred temporally appropriatepoint prior to) introduction into the patient.

Further, the present invention provides methods for sizing the length ofa capillary stem on a container having a primary hyperpolarized gasholding chamber with a volume, the capillary stem having a volume whichis substantially less than that of the gas holding chamber and includesa wall defining a flow channel aperture having a radius or width and alength. The wall has a gas-contacting surface formed of a materialhaving a relaxivity value for a selected hyperpolarized gas associatedtherewith. The method comprises the steps of defining a capillary stemaperture size; establishing a relaxivity value for the material formingthe capillary wall; and calculating an optimal capillary stem length.Similarly, the present invention can configure containers with capillarylengths chosen to increase the polarized life of the gas held therein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic illustration of the human circulatory systemillustrating the venous and arterial portions thereof. The deoxygenatedblood is represented by the lighter/white regions and the oxygenatedblood is represented by the darkened regions.

FIG. 1B is a schematic illustration of preferred anatomic injectionsites associated with MRI angiographic imaging regions according to thepresent invention. Region “A” represents the cranium, region “B”represents the lower extremities, region “C” represents the pulmonaryvasculature, region “D” represents the renal portion of the circulationsystem or vasculature, and region “E” represents the hepatic portion ofthe vasculature. Exemplary injection sites or delivery paths associatedwith the imaging regions are noted by the numeric subscript. Forexample, for pulmonary vasculature imaging region represented by theletter “C”, a first injection site C₁ and a second ventilation deliverypath C₂ are shown according to the present invention. In contrast, theremainder of the regions are shown with one or more injection sites.

FIG. 2 is a schematic illustration of a MRI system for pulmonaryembolism screening according to a preferred embodiment of the presentinvention. As shown, the subject is receiving two separate doses ofhyperpolarized gas, one of which is injected ¹²⁹Xe gas and one of whichis inhaled gas (ventilated).

FIG. 3A is a cross-sectional view of a vein.

FIG. 3B is a cross-sectional view of an artery.

FIG. 4 is a side view of different sized blood vessels illustratingdifferent flow rates corresponding to diameter of the vessel at aparticular pressure.

FIG. 5 is a schematic illustration of a controlled gas delivery systemaccording to the present invention.

FIG. 6 is a side view of an alternate controlled gas delivery systemaccording to the present invention.

FIG. 7A is a section view of the syringe taken along the line drawn as7A-7A in FIG. 6.

FIG. 7B is a side view of a hyperpolarized gas injection device with aNMR excitation coil mounted thereon according to the present invention.

FIGS. 8A and 8B are perspective views of yet another alternative gasdelivery system according to the present invention. FIG. 8A illustratesthe gas container with an inflatable inner membrane member. FIG. 8Billustrates the inner membrane member expanded to expel or force aquantity of hyperpolarized gas out of the chamber. FIG. 8B alsoillustrates a NMR monitor coil positioned to detect the polarizationlevel of the gas, preferably just prior to dispensing into the subject.

FIG. 8C is an enlarged end view of the exit surface of an injector headaccording to embodiments of the present invention.

FIG. 8D is a schematic drawing of an injection system according toembodiments of the present invention.

FIG. 8E is a schematic drawing of an alternative injection systemaccording to embodiments of the present invention.

FIG. 8F is an enlarged sectional view illustrating at least two separateflow channels and a mixing chamber upstream of gas outlet portsaccording to embodiments of the present invention.

FIG. 8G is a greatly enlarged partial side view of an injection headhaving a convergent nozzle configuration according to embodiments of thepresent invention.

FIG. 8H is a greatly enlarged partial sectional side view of an endportion of an injection head according to embodiments of the presentinvention.

FIG. 8I is a greatly enlarged partial sectional side view of analternate configuration of an end portion of an injection head accordingto embodiments of the present invention.

FIG. 9 is a graph of a timing sequence of a quantity of injected gas anda MRI pulse imaging sequence according to a preferred embodiment of thepresent invention.

FIGS. 10A-10P are graphs of NMR spectra obtained about every 0.5 secondsvia a whole body imager based on about a 3 cc polarized ¹²⁹Xe gasinjection into the vein of a rabbit (total of elapsed time from FIGS.10A to 10P being about 8 seconds). The graphs illustrate that the gasremained substantially in the gas phase (substantially insoluble as ittraveled through the bloodstream during the image acquisition). Thesignal strength at 8 seconds (FIG. 10P) being about 0.65 that of theoriginal signal (FIG. 10A).

FIG. 11 is a graph which illustrates a relationship which can assess anincreased, and preferably, optimum capillary length for containershousing ¹²⁹Xe. The graph shows a maximum or optimal T₁ obtained atparticular length and that for larger or smaller lengths, the T₁ isreduced over the T₁ obtainable at the optimal length. The samerelationship can be used to determine capillary lengths for ³He andthese lengths will be substantially longer for similar T₁'s andsimilarly sized containers and stem radiuses.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

The present invention now will be described more fully hereinafter withreference to the accompanying drawings, in which preferred embodimentsof the invention are shown. This invention may, however, be embodied inmany different forms and should not be construed as limited to theembodiments set forth herein; rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art. Likenumbers refer to like elements throughout. In the figures, certainlayers, regions, or components may be exaggerated or enlarged forclarity.

As known to those of skill in the art, polarized gases are collected,frozen, thawed, and used in MRI applications. For ease of description,the term “frozen polarized gas” means that the polarized gas has beenfrozen into a solid state. The term “liquid polarized gas” means thatthe polarized gas has been or is being liquefied into a liquid state.The term “gaseous” hyperpolarized ¹²⁹Xe indicates the gaseous phase ofthe “hyperpolarized ¹²⁹Xe gas”. Thus, although each term includes theword “gas”, this word is used to name and descriptively track the gaswhich is produced via a hyperpolarizer to obtain a polarized “gas”product. Thus, as used herein, the term “gas” has been used in certainplaces to descriptively indicate a hyperpolarized noble gas product andmay be used with modifiers such as solid, frozen, and liquid to describethe state or phase of that product.

Various techniques have been employed to accumulate and capturepolarized gases. For example, U.S. Pat. No. 5,642,625 to Cates et al.,describes a high volume hyperpolarizer for spin polarized noble gas andU.S. Pat. No. 5,809,801 to Cates et al. describes a cryogenicaccumulator for spin-polarized ¹²⁹Xe. U.S. Pat. No. 6,079,213 toDriehuys et al., entitled “Methods of Collecting, Thawing, and Extendingthe Useful Life of Polarized Gases and Associated Apparatus,” describesan improved accumulator, collection and thaw methods, and xenon gasheating means. The disclosures of these documents are herebyincorporated by reference as if recited in full herein.

As used herein, the terms “hyperpolarize”, “polarize”, and the like,mean to artificially enhance the polarization of certain noble gasnuclei over the natural or equilibrium levels. Such an increase isdesirable because it allows stronger imaging signals corresponding tobetter MRI (and spectroscopy) images of the substance and a targetedarea of the body. As is known by those of skill in the art,hyperpolarization can be induced by spin-exchange with an opticallypumped alkali-metal vapor or alternatively by metastability exchange.See Albert et al., U.S. Pat. No. 5,545,396. Other methods may also beused, such as dynamic nuclear polarization (“DNP”) and “brute force”methods which propose to cool the ³He or ¹²⁹Xe to very low temperaturesand then expose them to very high magnetic fields to enhance the thermalequilibrium polarization.

Generally stated, the present invention recognizes that direct gaseousinjection of hyperpolarized ¹²⁹Xe can be a viable, safe, and effectivedelivery method when the gas is formulated and delivered in a mannerwhich reduces the potential for formation of emboli within thevasculature. Unlike many previous injectable formulations, the presentinvention employs a gaseous formulation of inert polarized (preferably“isotopically enriched” polarized ¹²⁹Xe gas as will be discussed furtherbelow) ¹²⁹Xe which is packaged in a polarization friendly (increasedlonger relaxation life) container or syringe to provide an injectablepharmaceutical grade gas phase product. The gas phase injectableformulated hyperpolarized ¹²⁹Xe can be an effective image enhancingproduct when delivered at a controlled rate and/or quantity with apredictable polarization level which can provide improved imageresolution and/or diagnostic capability without the need for additionalliquid carrier agents and mixing. Direct gaseous injection has manyadvantages that can not only simplify the diagnostic procedure, it canalso restore the sensitivity of ¹²⁹Xe to its environment and can improvethe delivery efficiency of polarized ¹²⁹Xe to target tissues. Thegaseous injection can be performed such that it remains substantiallynon-dissolved in the bloodstream over about 8-10 seconds from the timeof injection, or can be performed such that it is at least partially,and even substantially, dissolved proximate to the injection site orwithin a short period from the time of injection (i.e., less than about2-4 seconds).

Further, in certain embodiments the gaseous formulation can eliminatethe use of an external fluid-mixing step. Still further, thehyperpolarized ¹²⁹Xe can be contained in a specialized gas syringe withincreased relaxation times as will be discussed further below. Incertain embodiments, the degree of polarization is measured via an NMRcoil located on the dispensing container itself which can be utilizedjust prior to administration. Thus, the NMR signal strength can be moreaccurately/reliably correlated to the polarization level and also theadministration can be performed in a relatively calm, relaxed manner,without the impending threat and constraints of rapid decay elicit inmany conventional short T₁ formulations.

Referring now to FIG. 1A, a human circulatory system 10 is schematicallyillustrated. The oxygenated blood within the vasculature is representedby the darker regions while the deoxygenated blood is represented by thewhite or lighter regions.

As used herein the term “vasculature” includes boundary tissue, cells,membranes, and blood vessels such as capillaries, venules, veins,arteries, arterioles, and the like associated with the circulatorysystem and blood flow path and/or channels of blood. Typically, as shownin cross sectional views in FIGS. 3A and 3B, the artery flow channels 30a are smaller and more rigid and round compared to the vein flowchannels 30 v.

The gaseous ¹²⁹Xe injection of the present invention has somesimilarities to a technique presently used, called digital subtraction(DSA) CO₂ angiography. Generally described, in this conventionalprocedure, CO₂ is rapidly injected to displace a portion of the blood.An X-ray image is taken quickly after injection. Where the CO₂ hasdisplaced the blood, there is reduced X-ray opacity and the imageappears brighter. Typically, a second X-ray is taken without CO₂injection and the two images are digitally subtracted to show thecontrast. CO₂ DSA is used instead of traditional iodinated contrastagents because of the “nephrotoxicity” of iodine-based contrast agents.The volumes of CO₂ injected range from roughly 10 cc's to 50 cc's (thelarger quantity for larger blood vessels). In addition, the injectionrate is quite rapid (10 ml/s to 100 ml/sec) inasmuch as contrast onlyresults from the displacement of blood. Generally stated, afterinjection, CO₂ is efficiently dissolved into the blood and exhaled uponpassage through the pulmonary capillary bed. Stated differently, CO₂exits the blood into the lung alveoli via diffusion through pulmonarycapillary. A review of this technique has been presented by Hawkins andco-workers. Kerns et al., Carbon Dioxide Digital SubtractionAngiography: Expanding Applications and Technical Evolution, 164 Am.Jnl. Radiology, pp. 735-741 (1995).

The feasibility of gaseous ¹²⁹Xe injection, particularly for arterialinjections, may appear problematic. For example, it is known thatarterial injections of air can lead to an undesirable air embolus.Although with intravenous (IV) injection the introduction of air is lessof a concern, great care is typically taken to avoid such occurrences.The injection of CO₂ is successful because of its high solubility inblood and the body's unique ability to remove it. The solubility of CO₂in blood and plasma can be difficult to measure because it is chemicallymetabolized. However, its solubility in water is 0.63 and it has beenmeasured in RBC (red blood cell) ghosts to be about 1.0. Table 1 belowshows the solubilities of other relevant gases in water plasma andblood.

TABLE 1 Solubilities of Gases Gas Water Plasma Blood Other He 0.00980.0086 0.0094 0.0105 (lung) N₂ 0.0143 0.0134 0.0148 0.109 (RBC ghosts)O₂ 0.0271 0.0243 0.0261 0.13 (RBC ghosts) CO₂ 0.631 — — 1.0 (RBC ghosts)Xe 0.089 0.105 0.167 0.181 (liver)

As CO₂ in plasma and blood are metabolized before the measurements canbe obtained, no numbers are listed for these entries in Table 1.Nonetheless, it is believed that the solubility that is of primaryinterest for the discussion herein and that the CO₂ metabolism can bedisregarded for the purposes of this comparison.

Table 2 below shows the solubilities of these gases relative to CO₂(i.e., the relative solubility “S_(r)” is represented by the ratio of:

(Solubility of named gas in water)/(Solubility of CO₂ in water).

TABLE 2 Relative Solubility (S_(r)) Gas Sr (relative) CO₂ 1 Xe 0.14 O₂0.043 N₂ 0.023 He 0.016

Table 2 illustrates the higher solubility of xenon compared to the majorconstituents of air (O₂ and N₂) but also shows that CO₂ is considerablymore soluble than xenon. Therefore, the present invention recognizesthat direct gaseous injection of polarized ¹²⁹Xe can be a useful in vivodiagnostic NMR imaging tool and also recognizes that proper sizing ofthe injectable quantities and/or the injection rates are importantconsiderations for achieving same. Accordingly, the present inventionprovides a maximum preferred arterial xenon injection volume bycomparing the solubilities of xenon and CO₂. Maximum CO₂ injectionvolumes are typically limited to about 50-100 cc's of gas. By taking therelative solubilities above into consideration, the maximum xenoninjections can be predicted to be about 0.14 times the quantity orvolumes of CO₂. Thus, particularly for arterial injection sites, for aCO₂ volume of 100 cc's, the xenon injection volume is preferably limitedto about 14-20 cc's. For the smaller range of injected CO₂, such as a 10cc injection volume, a 1.4-2.0 cc volume of polarized ¹²⁹Xe gas ispreferably dispensed according to the present invention.

In contrast, for non-arterial sites, such as for venous injection sites,a larger injection quantity may be tolerated. That is, it is known thatthe introduction of air into venous sites which is on the order of300-400 cc's can be particularly troublesome and even potentially fatal.Xenon, although less soluble in blood than CO₂, is about 10 times moresoluble than air (i.e., it can dissolve faster in blood than air). Thus,even with a safety factor, the venous site injections can be typicallysized at quantities in the range of about 100 cc's, although preferablysized at less than 100 cc's. Of course, such injection volumes alsodepend on the vessel type and size being injected into.

Along with the quantity of the gas formulated for injection, thegenerated bubble size and/or bubble dissipation can be importantconsiderations for in vivo applications, particularly for arterialinjection sites. In certain embodiments, a surfactant can be injectedproximate in time and location to the gas injection site to either helpdissipate the size of the bubble and/or to lower the blood surfacetension. Surfactants have been studied by van Blankenstein et al. to aidin the recovery from venous air embolism. See J. H. van Blankenstein etal., Cardiac Depression after Experimental Air Embolism in Pigs: Role ofAddition of a Surface-Active Agent, 34 Cardiovascular Research, pp.473-482 (1997). In this study, air bubbles with a diameter of about 150μm were injected into the left anterior descending coronary artery inthe presence or absence of antifoam. A 1:250 dilution of siliconeantifoam 1510 EU (from Dow Corning) in pure water was used. The studyindicates that the in vivo introduction of surfactants can reduce bubbledissipation time in blood.

It is contemplated by certain embodiments of the present invention thatany suitable in vivo physiological compatible or acceptable surfactantcan be employed whether of natural (human or bovine) or syntheticorigin, and/or combinations thereof. Suitable physiologically acceptableformulations are known to those of skill in the art. See e.g., U.S. Pat.No. 4,826,821 to Clements, U.S. Pat. No. 4,312,860 to Clements, and U.S.Pat. No. 5,309,903 to Long (all discussing the use of surfactants invivo for respiratory distress syndrome). These disclosures are herebyincorporated by reference as if recited in full herein. See also Horbaret al., A Multicenter Randomized, Placebo-controlled Trial of SurfactantTherapy for Respiratory Distress Syndrome, 320 The New England Jnl. ofMed., No. 15, pp. 959-965 (Apr. 13, 1989) (discussing organic solventextract of cow-lung fortified with dipahnitoylphos-phatidlydhloine knownas “SURVANTA” from Abbott Laboratories in Chicago, Ill.). Preferably,the surfactant is also chosen such that it is substantiallynon-depolarizing to the hyperpolarized state of the gas. The surfactantmay be delivered via injection or insertion into the body proximate tothe target gas injection site such that it facilitates bubbledissipation or reduces blood surface tension while also beingsubstantially non-depolarizing to the polarized state of the gas (tohelp reduce the formation of emboli attributed to the injected gas).

As briefly discussed above, the injection of the gas can be carried outin a manner which reduces or limits the bubble size associatedtherewith. To better understand bubble dissipation, one can model astring of contiguous bubbles as a cylinder to look at the diffusion ofthe gas out of the “cylinder” into the surrounding fluid to analyze howthe bubble volume or radius decreases with time. Presser et al., inmodeling a simulation as stated above, noted that the bubble radius “r”versus time can be represented by the equation:

dr/dt=−KΔP/[r ln(R/r)]

where “K” is Krogh's coefficient (the product of solubility “S” anddiffusion coefficient “D” of the gas in the surrounding fluid), “ΔP” isthe pressure difference between gas in the bubbles and gas in thealveoli and “R” is the distance from the center of the bubbles to theinner edge of the adjacent alveoli. See Presser et al., Fate of AirEmboli in the Pulmonary Circulation, 67 J. Appl. Physiol. 5, pp.1898-1902 (1989). To solve the equation requires numerical techniques,but the relationship can be generally characterized as beingsubstantially linear for air down to about a 10 μm radius bubble, atwhich size the rate of dissipation is increased (i.e., it becomessteeper and more exponential-like). Presser et al. also notes that forair bubbles with radius' greater than about 10 μm, dr/dt=−0.132 μm/s.Thus, generally speaking, a 30 μm radius air bubble takes about 230seconds to dissipate.

In contrast, as recognized by the instant invention, xenon bubbledissipation occurs at a faster rate than air. That is, for comparativeanalysis, it is believed that one can evaluate the Krogh's coefficient(S×D) for Xe relative to air. The diffusion coefficient is substantiallythe same and can be cancelled out. For example, Xe in H₂O is about1.9×10⁻⁵ cm²/s while methane and water itself are at 2 and 2.3×10⁻⁵cm²/s, respectively. Thus, solubility “S” becomes the important factor.Therefore, approximating air as nitrogen, the solubility ratio of xenongas to nitrogen gas in blood is (0.167/0.0148), or about eleven (11).Accordingly, the bubble dissipation rate (dr/dt) for xenon is estimatedat −1.5 μm/s. The same 30 μm radius bubble will dissipate in about 20seconds. This additionally supports the direct injectability of ¹²⁹Xepolarized gas into systemic arterial and venous circulatory injectionsites.

Air bubbles of various sizes have been produced for injection into acoronary artery. See Van Blankenstein et al., Heart Function afterInjection of Small Air Bubbles in Coronary Artery of Pigs, 67 J. App.Physiol. 5, pp. 1898-1902 (1989). In this study, air bubbles of 75, 150,and 300 μm diameter were formed with tolerances of about 10 μm.Generally stated, a micropipette with a constant-pressure source of airwas used to form the desired bubble size. Factors impacting theformation of bubble size were pipette diameter, air (gas) pressure, andthe flow of fluid through the pipette (flow volume in the artery mayalso be parameter to be considered). It is anticipated that calibrationcurves can be generated based on these factors (i.e., bubble-sizedependent variables) to generate the desired bubble size.

In any event, in certain embodiments, the hyperpolarized ¹²⁹Xe gas canbe directly injected into the subject, such as into the blood stream ofthe subject, in bubble-sizes in the range of between 1 nm to 300 μm, andpreferably in the range of between about 0.5-10 μm.

In order to generate a series of sequential bubbles for injection, it ispreferred that a frit or custom fabricated lumen (small diameter)configuration can be employed and/or with a controlled pressure set toform the desired bubble size (not shown). In certain embodiments, thefrit may comprise glass (such as a substantially magnetically purealuminosilicate or surface coated glass to reduce surface relaxationeffects). A differently sized/configured frit (exit diameter/shape) orlumen may be formed for various injection sites (particularly tofacilitate the production of smaller bubble size for arterialapplications) and located such that it is in fluid communication withthe conduit or even integrated into the syringe or IV or other catheterbody itself.

In any event, a polarized ¹²⁹Xe gas injection quantity of as low asunder 5 cc's, such as just 1-2 or 1-3 cc's, but typically at least about14-20 cc's (depending upon the injection site), can provide improvedsignal strengths even over larger amounts with conventionalhyperpolarized inhalation techniques (although greater quantities can beused as discussed above). For example, the brain-imaging exampledescribed above shows that an injection of just 1, 2, or 3 cc's of ¹²⁹Xecan result in larger signals than can be typically achieved throughinhalation of 1 liter of hyperpolarized ¹²⁹Xe. The signal strength canbe improved to be even stronger if isotopically enriched polarized ¹²⁹Xeis employed.

Furthermore, unlike injection of CO₂, the ¹²⁹Xe injection does not haveto be performed at a rate which is fast enough to displace the blood.The ¹²⁹Xe can be readily imaged if it is (a) dissolved in the blood, or(b) if it remains (largely or in smaller amounts) in the gas phase as ittravels in the bloodstream for imaging purposes.

In the case of an arterial injection where rapid dissolution of thexenon into the blood stream may be desired, the gas injection can beperformed at a rate which is sufficiently slow so that the xenon cansubstantially dissolve into the blood stream as it is injected therein.Mathematically stated, this injection rate limit may be set at about

${\frac{}{t}V_{Xe}} = {\lambda \; Q}$

where “λ” is the xenon solubility in blood and “Q” is the volumetricblood flow rate in the vessel being injected. Injection at this speedcan result in substantially fully xenon-saturated blood in the injectionregion. In certain embodiments, the injection rate can be selected suchthat it is less than the blood flow rate within the injection site. Theinjection rate can be carried out such that it is less than about 25-50%of the blood flow rate, particularly for arterial injection sites. Forexample, blood flow in the hepatic artery in an average adult is roughly5.8 cc/s, so it is anticipated that a xenon gas injection rate of about1-5 cubic centimeter per second (cc/s), and in certain applications 2.9cc/s or less, or in other applications about 1 cc/s or less should bephysically tolerable and sufficiently rapid to deliver a quantity whichcan yield clinically acceptable NMR images and/or signals.

FIG. 4 illustrates three different flow rates and associated vesseldiameters (at flow rates smaller than the hepatic artery described above(5.8 cc/s=348 ml/min)). Of course, especially for more distal targetimaging regions and/or smaller injection quantities, or where isdesirable to retain a larger portion of the gas non-dissolved in thebloodstream, faster injection rates can be employed.

Venous injections using even larger xenon volumes or quantities and/ormore rapid ¹²⁹Xe injection rates (as well as larger bubble size) ascompared to the arterial injection sites may also be suitable. Forexample, for 100 cc's of injectable gas, a suitable injection rate canbe about 2-3 cubic centimeters per second. In other applications, ratessubstantially equal to or less than about 2 cc/s may be appropriate. Theinjection rates can be controlled in a number of ways such as via manualor automated (or semi-automated) operation as will be appreciated bythose of skill in the art. See e.g., U.S. Pat. No. 3,623,474 to Heilmanet al. and U.S. Pat. No. 5,322,511 to Armbrusther et al. (describingpower injection equipment). The contents of these documents are herebyincorporated by reference as if recited in full herein.

In contrast to inhalation methods, the gas-injection method allowssmaller amounts of hyperpolarized gas to be effectively administered insmaller clinically effective doses. This smaller dose gas-basedadministration also allows for a commercially advantageous use ofisotopically enriched (typically more a expensive formulation) polarized¹²⁹Xe. “Isotopically enriched” means ¹²⁹Xe which has been enriched overnatural levels (the natural level is about 26%). Preferably, the ¹²⁹Xegas which is polarized is enriched to a level which is isotopicallyenriched to at least about 50%, and more preferably enriched to at leastabout 70%, and still more preferably enriched to at least about 80%.

The present invention now allows the arterial side of the pulmonaryvessels to be directly imaged rather than inferring or predictingventilation defects vicariously as proposed in conventional inhalationbased systems. That is, as discussed above, injection into a vein,allows the polarized gas to travel in the bloodstream through the heartand then into the pulmonary artery. In contrast, inhalation allowsventilation-based images and then as the polarized gas travels into thebloodstream through the pulmonary vasculature, it travels into thepulmonary venous circulatory flow path and can allow signal informationcorresponding to the venous system.

Still further, the imaging techniques which employ direct injection ofhyperpolarized gas can provide perfusion images which are unobscured byventilation defects typically associated with conventionalinhalation-based images. That is, the inhalation methods may show aperfusion defect where a ventilation defect resides, because gas may beblocked from entering the vessels. In contrast, direct gas injectionmethods of the present invention can show “real” perfusion defects,i.e., defects attributed (solely) to perfusion blockage. In addition, asnoted above, using both inhalation and injection delivery of polarizedgas as described herein can provide complementary diagnostic informationand detail.

It should also be noted that NMR imaging or signal acquisition of ¹²⁹Xein the gas phase in the blood can provide increased an increased T₁ overthat of the gas dissolved in the blood. In addition, ¹²⁹Xe dissolvedinto the blood may provide a broader spectrum attributed to the rapidexchange between the ¹²⁹Xe in RBC's and plasma. Unfortunately, a broadspectral line typically translates to a relatively short T₂*. Therefore,sizing and delivering the injectable dose so that it remainssubstantially as a gas in the bloodstream can allow longer dataacquisition times and/or improved images or signals therefrom.

Of course, the injection rate or release rate (volume over time) can beselected such the polarized gas is solubilized (substantially dissolved)into the blood proximate to the injection site. Alternately, theinjection rate can be selected such that the gas is only partially orinsubstantially solubilized in the blood proximate to the injection siteor such that it remains in a non-dissolved state for a longer period oftime as it travels through the bloodstream. For example, introducing thehyperpolarized gas into a vein (through the walls of the vessel) suchthat it retains sufficient polarization to render a clinically usefulgas-phase signal after about 8-10 seconds, and preferably after about8-20 seconds, from the time of injection. Maintaining the hyperpolarizedgas in the gas phase (such that it is not substantially dissolved intothe bloodstream) can increase the T₁ of the gas in the body. This, inturn, can allow longer image acquisition times during which the signalcan be picked up as a viable clinically useful diagnostic tool. Again,the venous injection sites can generally withstand a greater injectionvolume and/or a greater delivery rate than a similarly sized arterialvessel.

Indeed, in the past, about 1 ml of air in 10 ml of saline was injectedinto the right internal jugular (IJ) vein of a human and monitored withultrasound for IJ valve competence. See Ratanakorn et al., Jn. OfNeuroimaging, Vol. 9, pp. 10-14 (1999). It is expected that about 1-10ml of hyperpolarized ¹²⁹Xe gas, preferably configured with reducedbubble sizes (preferably at about or less than 10 microns) injected intothe U will also yield clinically useful images and/or spectra (thehyperpolarized xenon gas bubble dissipation being about 11 times fasterthan air in blood as discussed above).

FIG. 1B schematically illustrates suitable injection sites (shown byasterisks located on the body and a corresponding circled letter) and anassociated particular tissue, organ, or vasculature target region (shownby dotted line box with and a corresponding letter identification)according to certain embodiments of the present invention.

Target Region of Interest Preferred Injection Site Region A CraniumNeck-Carotid Artery Region B Lower Extremities Thigh-Femoral ArteryRegion C Pulmonary Arm, Vein (preferably in conjunction with ventilatedgas) Region D Renal (Kidneys) Renal Artery Region E Hepatic (Liver)Hepatic Wedge Region A Cranium Right internal juglar artery (IJ)

For example, as shown by the two circle “C” delivery sites, thepulmonary region preferably employs both an injection site to a vein inthe arm to deliver gaseous ¹²⁹Xe and an inhalation delivery of polarizedgas (the inhalation being either ¹²⁹Xe or ³He, more preferably ¹²⁹Xe).Of course, the present invention is not limited to the injection sitesand target regions disclosed above, as additional or alternate sites andadditional or alternative target regions can also be employed. Indeed,internal injection or release sites can also be employed such as throughthe use of special catheters (threaded to the desired injection ordelivery site) to deliver gas phase ¹²⁹Xe to desired target regions aswill be appreciated by one of skill in the art.

Certain embodiments of the present invention are directed to the use ofinjected gaseous polarized ¹²⁹Xe for the detection of pulmonaryembolism. In these embodiments, the xenon is injected into a vein,preferably via an intravenous catheter inserted into a vein in the armand, after a suitable delay, an image of the xenon in the arterialpulmonary circulation can be made to determine if an embolus is present.For example, about 50-100 cc's of gas are injected and after about 5-25second delay period, preferably about a 5-7 second image delay period(the delay period being measured from the time after injection stops)scanning is initiated. Preferably, the scanning, based on thisinjection, is completed in less than about 60 seconds, and preferably,in about 10-45, and more preferably in about 10-20 seconds.

Alternatively, a longer delay can be applied between the time ofinjection and the image data or signal acquisition or collection so thata scan can be made of the gaseous ¹²⁹Xe as it enters in the lungresulting from the venous injection, as the gaseous ¹²⁹Xe injected in avein in the arm will subsequently dissolve only to appear or enter intothe lung if circulation is not blocked in the pulmonary arteries. Inaddition, even if the blockage is not severe enough to prevent the ¹²⁹Xewhich is injected in gas phase from entering the lung, the signalintensity of this transitory ¹²⁹Xe in the lung can vary depending on thedegree of restriction (brighter signal for smaller restrictions or freepassage, and reduced signal intensity in the lung void space for blockedor substantially restricted blood circulation passages).

In certain embodiments, such as for the lung void space image, as iswell known to those of skill in the art, suitable contrast mechanismssuch as chemical shift, T₂*, diffusion, etc., can be used to distinguishbetween imaging segments which include the gaseous ¹²⁹Xe in the lung andversus (and preferably excludes or extracts) the signal data associatedwith the ¹²⁹Xe still dissolved in blood.

In certain embodiments, the pulmonary circulation image scan based onthe gas injection is coupled with a ¹²⁹Xe or ³He pulmonary ventilationscan. Using a ¹²⁹Xe ventilation scan may be preferable, because itallows the same MRI transmit/receive coil to be used for the entireprocedure. The ventilation scan can be employed regardless of thedissolution or lung based image rendering methods employed on thegaseous injected polarized ¹²⁹Xe. The coupled scan can identify a V/Q(volume versus flow rate in the circulatory system) mismatch and providea potential diagnostic tool for the clinician. Alternatively, if ³He isused for the ventilation image, it is preferred that the chest coil beconfigured as a “double tuned” coil. That is, the double tuned coil istuned to operate for both ³He and ¹²⁹Xe operation.

In addition, it is preferred that the chest coils be configured to be“proton blocked” allowing the MR scanner body coil to be used to make aproton image of the subject in substantially the exact same position asthe subject during the V/Q image. Thus, the proton blocked chest coilallows the body coil to obtain supplemental proton-based data image(without the interference of the polarized gas based coil) which can becombined in a signal processor with the V/Q signal data to provide amore detailed diagnostic evaluation of the target region of interest. Ofcourse, the proton-blocked configuration of the gas based imaging coilcan be operated with respect to the other gas-based images describedherein.

In certain embodiments, the inhalation based image is generated usingpolarized ¹²⁹Xe while the perfusion image is also generated using theinjected gaseous polarized ¹²⁹Xe. An NMR system with a low field magnetmay be used (such as about 0.1 T-0.5 T), and the pulmonary region imagemay provide increased signal intensity from the NMR resonance signalsresulting from both the dissolved and gas phase xenon in the pulmonaryregion (two peaks, one associated with the RBC's and one with theplasma). Reduction of field strength can sacrifice chemical shiftinformation between the dissolved phase and gas phase xenon in thetarget region. Nonetheless, the advantage of low-field imaging of ¹²⁹Xein blood is that the separate peaks of ¹²⁹Xe in RBCs versus plasma willoverlap and yield a larger total signal than at high-field where ¹²⁹Xein blood or plasma is separately excited and imaged.

Alternatively, a larger field magnet (>0.5 T) can be used whichseparately excites the dissolved phase and gas phase polarized gaspresent in the region of interest, and two or more data sets arecaptured via one or more excitation pulses (such as two separate imagingsequences operated at two different excitation frequencies). In thisembodiment, due to the chemical shift between the gas and dissolvedphase resonance (approximately 200 p.p.m. at 1.5 T), at least two images(both a perfusion and ventilation image) are generated on a patientduring the same imaging session (“differential” imaging). A differentialimage can provide additional diagnostic information over combined phasesignals. For example, the differential image can help distinguishbetween a pulmonary embolus and a ventilation/perfusion defectassociated with a structural anomaly as described above.

In operation, for MR images using ¹²⁹Xe as both the inhalation andperfusion medium, a first delivery of a first quantity of hyperpolarizedgas can be administered to a subject such as via injection. After asuitable, short, delay corresponding to the desired target imagingregion (a delay corresponding to the time it takes the hyperpolarizedgas to travel to the desired imaging site from the injection site), ascanning sequence can be initiated. For imaging the chest region (orregions affected by the position of the chest during breathingactivities), it is preferred that the patient hold his or her breath tohelp with locational co-registration between images (especially betweeninjection based and ventilation based images). Image signal dataassociated with the injected polarized gas according to the presentinvention is obtained before the polarization of the gas has decayed toan undesirable level (preferably within about 1 minute, and morepreferably within about 25 seconds from the time of injection). One ormore additional quantities of hyperpolarized ¹²⁹Xe can be subsequentlyinjected as needed. That is, a series of small injections (or smallreleases to an in situ catheter) can be made which allow a correspondingseries of data collection based on the image signal data associatedtherewith.

After the injected polarized gas has cleared the target region (or thepolarization has decayed to a point where it does not interfere with theventilation image), the ventilation delivery can commence. That is, asecond delivery of a second quantity of hyperpolarized gas isadministered. Because the second delivery is an inhalation delivery, thequantity of gas delivered is relatively large compared to the injectablequantity (about 0.75-1.5 liters versus less than about 20-100 cc'sdepending on the site). In operation, the subject inhales the secondquantity and holds his or her breath (typically for about 15 seconds).In certain embodiments, the injection based and ventilation based MRimages (or spectroscopic analysis) can be obtained during the sameimaging session, reducing co-registration issues associated withrelational positioning/re-positioning. In addition, separate (temporallyspaced apart from the injections) breath-hold delivery cycles may beused for ventilation images and perfusion directed images, which canthen be digitally combined with the injection signal data to provide amore complete image of the region.

In certain embodiments, where the pulmonary region is the target imagingregion, the combined image may be based on at least two differentadministrations of polarized gas: (a) direct injection of polarized gasinto a vein and (b) inhalation of polarized gas. These two differentadministrations can result in three different delivery mechanisms ofpolarized ¹²⁹Xe to the pulmonary (perfusion from the ¹²⁹Xe in the bloodand tissues delivered from a venous injection to the arterial side ofthe circulatory system, perfusion into the vasculature from the inhaledgas delivered to the venous side of the circulatory system, and aventilation image before, during, and/or subsequent to the perfusionimage with the same or additional quantities of inhaled gas).

In any event, differential imaging can provide MR images withinformation which correlates to the total region (lung space, artery andvein, and boundary regions). This technique can produce MR images whichallow diagnostic detection of emboli, perfusion defects, ventilationdefects, and other circulatory and/or respiratory system problems in thepulmonary vasculature.

In addition, for studies used to evaluate pharmaceutical effectiveness,the gas may be injected without regard to the toxicity or survivaloutcome. Indeed, the injection of hyperpolarized ¹²⁹Xe into a specifictarget region can allow the efficacy of a pharmaceutical drug, compound,or mixture, or drug therapy aimed at a particular disease or organfunction to be evaluated and or confirmed (post mortem) that such drugis actually delivered to the appropriate site and/or that it has aninfluence on the targeted condition. For example, a treatment directedto cerebral disorders can be evaluated for effectiveness in suitableanimal studies by comparing the injected hyperpolarized-gas based imageof the brain over time. Similarly the effectiveness of treatment onpulmonary or cardiac functions, blood flow, or neurological conditionsand the like, may also be evaluated. In one example, targeted genetherapy directed to increasing blood vessel growth at the heart can bedelivered. Subsequently a quantity of ¹²⁹Xe gas can be injected toprovide NMR signal based on the increased xenon associated withincreased blood vessels at the target site to confirm the success of thedirected gene therapy.

In addition, it is expected that small quantities of injectedhyperpolarized ¹²⁹Xe can provide additional safe and effective in vivodiagnostic assistance in evaluating the presence or absence of cancer inmammalian subjects, particularly humans (i.e., cancerous tumor or benigncyst). For example, in vivo cancerous tumors can be characterized by thepresence of increased random blood vessel growth (a condition known asangiogenisis). This is in contrast to benign cysts. Taking advantage ofthis characteristic and the NMR signal information available usingdirect ¹²⁹Xe polarized gas injection, a target in an organ such as atumor in a breast can be analyzed in vivo. In operation, a needle can beinserted or injected to the suspect region in the breast viaconventional MR guided needle placement and ¹²⁹Xe can be releasedthereat (along with or in lieu of removing biopsy materials). Signaturepeaks in spectroscopy signals can indicate the presence of cancer viathe increased peak in the signal due to the increased blood (and xenon'ssolubility therein). In obtaining the signal or images, an appropriatefield strength should be used so as to differentiate the peaksassociated with xenon in blood versus xenon in fatty tissue as will beappreciated by one of skill in the art. Of course, other contrastmechanisms like chemical shift, T₂* and the like, can also be employedto exploit the ¹²⁹Xe image signal in the tumor.

Referring to FIG. 2, in a preferred embodiment, a patient is positionedin a MRI system 25 and exposed to a magnetic field associated therewith.The MRI system 25 typically includes an NMR image processing system 26,a super-conducting magnet (not shown), gradient coils (with associatedpower supplies) (also not shown), an excitation coil (transmit/receiveRF coil) 30. Preferably, the coil 30 is configured as Helmholtz pairsoriented at 90 degrees relative to each other (not shown). Of courseother configurations can also be used such as Helmholtz coil or asurface coil for imaging near surface regions of the subject. The systemalso includes a RF amplifier for generating RF pulses set atpredetermined frequencies (also not shown). For ¹²⁹Xe imaging at 1.5 Tfield strength, the MRI imaging system 25 is set to operate in thegas-phase at about 17.6 MHz. For high field applications, the dissolvedphase excitation frequency is shifted below the gas phase excitationfrequency. For example, the dissolved phase excitation frequency isshifted to be about 200 p.p.m. lower than the gas phase excitationfrequency (corresponding to the chemical shift). Thus, at 1.5 T, thedissolved phase ¹²⁹Xe RF excitation frequency is about 3.52 kHz lowerthan the associated gas-phase excitation frequency. In yet anotherpreferred embodiment, the imaging method employs a 17.6000 MHz gas phaseexcitation pulse and an associated dissolved phase excitation pulse ofpreferably 17.59648 MHz. Of course, the magnet field strength andexcitation frequency can vary as is well known to those of skill in theart.

In any event, in operation the RF pulse(s) is transmitted to the patientto excite the nuclei of the polarized ¹²⁹Xe. The coil 30 is tuned to aselected frequency range and positioned adjacent the targeted imagingregion to transmit the excitation pulses and to detect responses to thepulse sequence generated by the MRI imaging system 25. The coil 30 shownin FIG. 2 is positioned to image the pulmonary vasculature region 12(FIG. 1A). Preferred coils 30 for standard chest imaging include awrap-around coil with conductors positioned on both the front and backof the chest. Examples of suitable coils known to those of skill in theart include a bird cage configuration, a Helmholtz pair or quadratureHelmholtz pairs, a surface coil, and a solenoid coil. The RF excitationcoil 30 is operably associated with the NMR image processing system 26for exciting and transmitting image signal information from thepolarized gas back to the NMR image processing system 26.

As noted above, once in position, the patient inhales a (predetermined)quantity of polarized ¹²⁹Xe gas into the pulmonary region (i.e., lungsand trachea). Preferably, after inhalation, the patient holds his or herbreath for a predetermined time such as 5-20 seconds. This is describedas a “breath-hold” delivery. Examples of suitable ventilation orinhalation delivered “single dose” quantities of polarized gases forbreath-hold delivery include 0.5, 0.75, and 1.0 liters of gas.Preferably, the dose at inhalation contains gas with a polarizationlevel above 5%, and more preferably a polarization level above about20%.

The MRI imaging system 25 shown in FIG. 2 includes a dual dose deliverysystem 38. Thus, as shown, the dual dose delivery system 38 preferablyincludes both an inhalation dose bag polarized gas supply 35 and aninjectable gas dose ¹²⁹Xe supply 40. Preferably, a non-magnetic support45 is employed to hold at least the inhalation dose(s) of polarized gas.The inhalation dose bag 35 is suspended from the support 45 and a lengthof polarization friendly conduit 37 is in fluid communication with thedose bag 35 and a mask 36 positioned over the airways of the subject, sothat the subject can inhale the polarized gas, while positioned in themagnet, at the appropriate time. Preferably, the injectable dose 40 ispreferably engaged with a catheter or IV 42, and is positioned proximateto the subject to reduce the conduit length 41 necessary to connect thegas to the catheter lumen 42 (IV) inserted into the subject. FIG. 5illustrates an alternate injection site with the injected gas preferablydelivered to the patient at a controlled rate, pressure, and asubstantially controlled overall dispensed quantity.

One way to dispense the gas is to employ an inflatable bladderconfigured and sized to receive a major portion of the injected dose gasbag 40 (preferably configured to enclose the dose bag therein). Inoperation, at the appropriate predetermined dispensing time in theimaging cycle, a controller directs a compressor to fill the inflatablebladder to exert pressure onto the external walls of the flexiblepolymer dose bag. Air, gases or other fluids or liquids can also be usedto expand the inflatable bladder. Preferably, for preservation of thepolarization, deoxygenated water is used to reduce the migration of airinto the dose bag. Of course, air can also be used, as the inflatablebladder is preferably configured with discrete channels which are formedof a magnetic contaminant-free material such as rubber, elastomers, orother expandable materials which will act as a shield between the bagwalls and the air (i.e., the air does not directly contact the exteriorwalls of the bag 40). Preferred materials for the dose bag are describedin U.S. Pat. No. 6,128,918 and co-pending and U.S. patent applicationSer. No. 09/334,400, the contents of which are hereby incorporated byreference as if recited in full herein.

In any event, as the bladder expands, it increases the pressure itexerts onto the dose bag 40. Preferably, the bladder is symmetricallyconfigured with discrete enclosed air (or gas or fluid) channels suchthat opposing channels contact opposing sides of the bag to facilitate aconstant and substantially equal distribution of pressure without theinflatable medium directly contacting the walls of the dose bag 40. Inaddition, instead of discrete channels 40C, the inflatable bag 40Bitself can be sealed and inflate around the enclosed dose bag.

Also, whenever more than one delivery mechanism is employed to introducepolarized gas products to a subject, the MR imaging system 25 can beconfigured to include an audible or visual alert to coordinate thedispensing of the substances.

FIGS. 6, 7A and 7B illustrate another embodiment of a syringe injectiondelivery system 75 according to the present invention. As shown, thesyringe 90 includes a plunger 92, a primary chamber 94, capillary stem115, and LUER LOK flow member 116 with a valve 117. As shown in FIG. 6,the LUER LOK flow member 116 is connected on one side via the valve 117to a vacuum system 118. The valve configuration allows a vacuum to beintroduced to pull unwanted oxygen from the chamber to prepare thecontainer prior to gas introduction therein.

In the past, high purity/high grade nitrogen has been used to purge theoxygen from the hyperpolarized gas containers to reduce polarizationlosses attributed thereto. According to a preferred embodiment of thepresent invention, CO₂ gas can be directed into the gas holding chamberand then removed via a vacuum introduced thereto in a “gas-evacuate”cleansing cycle. This CO₂ based gas-evacuate container preparationmethod can remove depolarizing oxygen from the containers. Further, evenif residual traces of CO₂ remain in the chamber or passages, any CO₂injected with the hyperpolarized gas will be absorbed by the bloodrelatively quickly as noted above.

As the polarized gas contacts the primary chamber 94, the plunger 92,and the walls of the capillary stem 115 and lumen (during injection), itis preferred that they be configured from a polarization friendlymaterial. As used herein, the term “polarization friendly material”means materials which reduce the contact induced decay or relaxationassociated therewith, such as materials which have reduced solubility,permeability, or relaxivity values. Examples of suitable materials willbe described further below.

Accordingly, it is preferred that the primary chamber 94 and at leastthe bottom primary surface 92B of the plunger (the gas contactingsurface) be configured from a gas-contacting material which has a lowrelaxivity for ¹²⁹Xe. This material can comprise a high purity metalwhich is substantially free of ferrous and paramagnetic impurities. Asshown in FIG. 7A, the bottom surface of the plunger 92B is formed of alow-relaxivity material and a second peripherally (circumferentially)positioned seal 92S. See co-pending U.S. patent application Ser. No.09/334,400 and 09/528,750, for a discussion of materials, containers,and gas delivery systems, the contents of which are hereby incorporatedby reference as if recited in full herein. The sealing material can alsobe coated with a polarization friendly material or formed of materialsand fillers with reduced depolarizing influence.

Exemplary materials for the interior surface of the primary chamber bodyand/or bottom surface of the plunger material (or other gas contactingsurfaces such as capillary stems and conduits/catheters) includescertain polymers such as PE and nylon-6, and high purity glass(preferably high purity aluminosilicates) or quartz (or sol-gel coatedsurfaces (see e.g., PCT US98/16834 to Cates et al., entitled Sol-gelCoated Polarization Vessels), and high purity metallized surfaces(substantially free of ferrous and paramagnetic impurities)). If highpurity metal gas contacting surface materials are used, it is preferredthat the high purity metal surface be formed from one or more ofaluminum, gold, or silver. It is also preferred that any O-rings orseals used be coated with or formed from polarization-friendly materialsto protect the gas from contacting potentially depolarizing fillers andother materials used in many commercially available seals. Of course,the lumen 42L (FIG. 5) itself is also preferably formed such that atleast the gas-contacting surfaces are coated with a high purity metal.

As noted above, in one embodiment, the syringe 90 also includes acapillary stem 115 which is configured to separate the primary gaschamber 94 of the syringe 75 from the valve 117 (to reduce the exposureto same because outer components such as the valve 117 or conduit 41 canpotentially include depolarizing components). As such, the capillarystem 115 typically includes a reduced size diameter passage whichextends a distance between the chamber 94 and the LUER LOK flow member116, valve 117, and other components. Preferably, the capillary stem 115is formed of an aluminosilicate and is directly formed onto the end ofthe primary chamber 94. It is also preferred that the capillary stem 115is sized with a length which is at least about 10% the length of theprimary chamber, and more preferably at least 20% the length of theprimary chamber. For example, for a 10 ml syringe having a chamberlength of about 6 cm, the capillary stem has a corresponding length ofabout 6 mm. Of course, other configurations can also be used and thepresent invention is not considered to be limited thereto. For example,optimal or improved capillary stem sizing methods are discussed furtherbelow.

In one embodiment, to obtain about a relatively long T₁, the container100 includes a primary gas holding chamber which has a chamber volumewhich is substantially larger than the volume associated with thecapillary stem 115 (the chamber volume is preferably at least an orderof magnitude greater volume than the capillary stem volume). In thisembodiment, the capillary stem is configured with a length which isabout 6.9 cm. One may also configure the radius of the stem such that isat, or less than, about 0.3 cm.

Thus, in producing the injectable product container, the syringe 75 canalso be connected to the CO₂ source in conjunction with the vacuumsource (or separately) to direct CO₂ gas into the syringe along thepassage 115P in the capillary stem 115 so as to run a series of severalgas/evacuation or purge cycles to remove the oxygen and clean thechamber and capillary stem 115. The gas-evacuation preparation methodwill be discussed further below.

After the gas-evacuate cycle (or purge/pump cycles) the chamber 94 canbe finally evacuated and the valve 117 closed in preparation for fillingwith the hyperpolarized ¹²⁹Xe gas. Of course, the hyperpolarized gas canbe directed into the syringe chamber 94 at a later time or at a timeproximate to the evacuation step. In any event, once the desired volumeof gas is directed into the syringe 75, the valve 117 can be closed andthe syringe 75 transported to the patient. A catheter 42 can bepositioned and the lumen inserted into the patient in advance ofengaging the syringe to the conduit and opening the LUER LOK flow member116 to release the gas in to the in situ catheter 42 to deliver the gasat the appropriate time.

FIGS. 8A and 8B illustrate yet another system for controlling/and ordispensing hyperpolarized gas to a subject. FIG. 8A illustrates acontainer 100 with a primary valve 110, a primary gas holding chamber112, a capillary stem 115, and an expandable member 120. The primaryvalve 110 moves forward and rearward in response to rotation of the knob110R to open and close the passage defined by the capillary stem 115from the first port 116. A second entry port 125 is configured opposingthe capillary stem 115 in fluid communication with the primary gaschamber 112. Preferably, a secondary valve 130 operates to open andclose the second entry port 125. The expandable member 120 expands intothe primary chamber 112 when the valve 130 is opened and fluid isintroduced into the second entry port 125. The degree of expansion ofthe expandable member 120 corresponds to the quantity of fluidintroduced through the second port 125. A liquid, gas, or mixturethereof can be used to expand the expandable member 120.

In one embodiment, the expandable member 120 defines a barrier betweenthe polarized gas and the expansion medium; the expansion medium doesnot directly contact the polarized gas. Any suitable liquid or gas canbe used as the expansion medium, and for thin barriers which may allowthe medium to travel therethrough, nitrogen or deoxygenated water, orother substantially non-depolarizing fluids can be used as the expansionmedium. In addition, because the expandable member does contact thepolarized gas, it is preferred that it be formed of a polarizationfriendly (low relaxivity and low solubility) material for the polarizedgas held therein. For example, a material such as LDPE or deuteratedHDPE, or more preferably a high purity non-magnetic metal and the like,or other low-relaxivity material which has a low permeability for thehyperpolarized gas held in the chamber may be employed. See co-pendingpatent application Ser. Nos. 09/163,721 and 09/334,400. The contents ofthese documents are hereby incorporated by reference as if recited infull herein.

As shown in FIG. 8B, after filling the container 100 at a fill site witha desired quantity of hyperpolarized gas such as ¹²⁹Xe through the firstentry port 116, an injection means such as a matable conduit or chamberwith a direct inject needle/lumen, catheter or IV needle 119, 42L isconnected to the first entry port 116. In position, as shown thecontainer 100 can be oriented on its side so that the length of thedelivery or polarized gas dispensing path “L” away from the container100 can be reduced to reduce the potential exposure of the gas tocontaminants as it travels therethrough. In the embodiment illustrated,a controller 22 directs an air compressor 47 to inflate the expandablemember at a predetermined rate (preferably a constant rate). The primaryvalve 110 is opened and the polarized gas is allowed to exit the firstentry port 116 at a controlled rate into the injection path and into thelumen 42L. In addition, the capillary stem 115 of the container ispreferably configured such that once the gas is captured in the primarychamber 112, a major portion of the hyperpolarized gas in the containeris isolated away from potentially depolarizing components (such asfittings, valves, and the like) during transport and/or storage as notedabove. Of course, other flow control configurations can also beemployed. For example, filling a container having a valve in fluidcommunication with tubing to about 2 atm with polarized ¹²⁹Xe. The valvecan be opened and the pressure difference directs the gas into thetubing out of the container. Of course, over time, the flow rate due tothe pressure differential will drop.

The capillary stem 115 can be formed as an integral part of the valvemember 110 or as a separate component. For example, the valve 110 caninclude a body portion formed of glass such as Pyrex® or the like, andthe capillary stem 115 can be directly formed onto an end portion of thevalve 110. Alternatively, the capillary stem 115 can also be formed froma glass such as Pyrex® or an aluminosilicate, or other material toextend therefrom as a continuous body co-joined or fused to the lowerportion of the valve 110. The valve illustrated in FIGS. 8A and 8Bincludes a plug portion 110P which longitudinally translates to engagewith the lower nozzle end of the valve chamber 110N to close the flowpath when the valve is in the closed position. In the reverse, the valveplug 110 p moves away from the nozzle end 110 n to allow the gas to flowthrough the capillary stem 115 and the and in (or out) the entry port116.

Operationally, still referring to FIG. 8B, the capillary stem 115 isconfigured such that a major portion of the hyperpolarized gas, once inthe chamber 112, remains therein when the valve 110 is closed. That is,the dimensions and shape of the capillary stem 115 are such thatdiffusion of the hyperpolarized gas away from the container chamber 112is inhibited. Thus, the capillary stem 115 can reduce the amount ofexposure for a major portion of the hyperpolarized gas with the valve110 and any potentially depolarizing components operably associatedtherewith. In addition, the capillary stem 115 also provides a portionof the gas flow path 22 f therethrough. As such, the capillary stem 115includes an internal passage which is preferably sized and configured ina manner which inhibits the flow of gas from the chamber 112 duringstorage or transport while also allowing the gas to exit the chamber 112at its ultimate destination (injection site) without undue orsignificant impedance.

In sizing a capillary stem (which can be employed with any type ofcontainer housing hyperpolarized noble gas (such as that shown in FIG. 6or 8A or otherwise)) to optimize the T₁ of the ¹²⁹Xe gas held therein,the following analysis can be used. Generally stated, T₁ can berepresented by the following equation:

$T_{1} \approx \frac{V_{main}l_{c}}{2\; \pi \; {R_{c}\left( {{DR}_{c} + {\psi \; l_{c}^{2}}} \right)}}$

Reviewing the equation, it will be appreciated that as T₁∞ as R_(c)→0.Thus, the “best” capillary radius is none at all. However, this is notpracticable. Typically, a certain basic or minimum capillary radius isneeded, i.e., sufficiently sized, in order to allow gas to flow in andout of the capillary and for the main chamber to be successfullyevacuated. In addition, some design limit can be placed on the “gasconductivity” of the capillary. This aspect will be discussed furtherbelow. In any case, once a capillary radius or width has been chosen,the equation above can be used to determine an improved or “optimal”capillary length by differentiating the equation and setting it equal tozero. (Of course, the equations below can be used in the reverse toestablish a desired radius based on a particular length).

$\frac{T_{1}}{{lc}} = 0$

This yields a solution for the optimal capillary length represented bythe following equation:

$l_{c} = \sqrt{\frac{{DR}_{c}}{\psi}}$

Note that this solution for l_(c) sets the diffusion component ofrelaxation in the capillary equal to the surface-induced component ofrelaxation. Since the assumption of infinite depolarization rate at theend of the capillary is probably overstated, one can adjust (reduce) thedetermined or calculated capillary length a little shorter.

In order to calculate optimal capillary lengths, relaxivity values orestimates are needed. As a simple estimate, one can consider that an 180cc spherical chamber of GE180 glass has a relaxation times of about 40hr for ³He and about 2 hr for ¹²⁹Xe. Knowing the relationship of“A/V=3/R” for a sphere, one can determine the relaxivity ψ of GE180glass for both gases. The diffusion coefficients are noted for referencebelow.

Gas T₁ ψ D ³He 40 hr 8.1 × 10⁻⁶ cm/s  2.05 cm²/s ¹²⁹Xe  2 hr 1.7 × 10⁻⁴cm/s 0.065 cm²/sThe table above illustrates that optimal capillary lengths will be verydifferent for ¹²⁹Xe with its smaller diffusion coefficient and muchlarger relaxivity than ³He. Thus, this is preferably taken into accountwhen designing the ¹²⁹Xe capillary stem. For example, if we assume a 1mm capillary diameter, and use the values of relaxivity above, one canfind the following:

D l_(opt) ³He  2.05 cm²/s 111 cm ¹²⁹Xe 0.065 cm²/s  4.4 cmThus, for a ¹²⁹Xe syringe whose main chamber volume is about 20 cm³,using a 4.4 cm capillary of 1 mm diameter can yield a capillarycontribution to relaxation of T₁≈12 hr. Double the capillary lengthwould yield a T₁ of about 9.5 hr, and half the capillary length wouldyield a T₁ of about 9.5 hr. FIG. 11 is a graph which illustrates anoptimum capillary length (if one employs a stem with a length which iseither larger or smaller than the optimal length, the T₁ is reduced overthe T₁ obtainable at the optimal length)

In a preferred embodiment, the container 100 body (and the syringe body94) is substantially formed from quartz glass gas contacting surfaces(high purity Si—O₂), Pyrex®, aluminosilicate glasses such as GE180,CORNING 1720 or other long T₁ life silica based material. Transitionglasses may be used to make a transition between glass materials havingdifferent thermal expansion coefficients. For example, for containersusing multiple types of glass such as Pyrex®, body and GE180 stem orother portion, a transition glass (such as Uranium glass (typicallyabout 35% 235 U)) can be employed to join the two glasses and form thecontainer. A suitable glass valve is available from Kimble Kontes Valveslocated in Vineland, N.J.

As is shown in FIGS. 7B and 8B, it is also preferred that a smallexcitation NMR coil 230 be positioned onto the container primary body94, 112 and operably engaged with the NMR image system 26 via atransmit/receive line 26T. The NMR excitation coil 230 can be in theflow path as shown or located on the side, proximate the exit path(shown as 230 a in FIG. 8B). This can allow a calibration measurement tobe initiated just prior to dispensing the gas to the subject. Of course,the NMR coil 230 can be positioned in other locations along the body ofthe container, and the calibration measurement can be taken prior toengagement with the controller 22 or the like. In any event, theinjection dose containers of the present invention (such as item 100 inFIG. 8A, items 35 and 40 in FIG. 2, and item 75 in FIG. 6) can allowtransport of ¹²⁹Xe to the hospital from remote locations (by providingimproved T₁'s) and can also enable calibration of the gaseous dosagejust prior to injection.

FIGS. 8C-8I illustrate alternate embodiments of an injection deviceaccording to the present invention. As shown in FIG. 8C, an injectorhead 300 having a plurality of gas orifices 310 facing in the flowdirection can be used to administer the hyperpolarized ¹²⁹Xe gas to thesubject. The orifices 310 are sized and configured so as to dispense thegas into the subject in a fine dispersion. In certain embodiments, inoperation, the injector head 300 is configured to dispense a finedispersion or spray of gas having microbubble sizes under about 50 μm,and preferably substantially between about 0.5-10 μm.

In certain embodiments, the orifices 310 may have an aperture width ordiameter of about 1 nm-50 μm, and preferably a width which is about 10μm or less such as between about 10 nm-10 μm, between about 0.01-10 μm,or between about 0.01-1 μm to increase the surface area (and decreasethe volume) of the bubbles corresponding to the administered gas as itenters the tissue, blood, or selected region of the body. Decreasing thevolume and increasing the surface area of the bubbles as they enter theblood stream may promote increased rates of ¹²⁹Xe dissolution into theblood (while inhibiting aggregation into undesirable large bubblesizes). A discussion on certain aspects of nanojet configurations can befound in Moseler et al, Formation, Stability, and Breakup of Nanojets,Science, Vol. 289, No. 5482, pp. 1165-1169 (18 Aug. 2000); the contentsof which are hereby incorporated by reference as if recited in fullherein.

The injector head 300 can be formed in or inserted into a distal endportion of an intravenous or intrarterial catheter 340 as shown in FIG.8D. The injector head 300 may also be positioned at other locations inthe hyperpolarized gas flow path (such as at a position with is externalof the body upstream of the entry point into the subject in the catheteror in a conduit connected thereto).

As shown in FIG. 8D, the injector head 300 is in fluid communicationwith a source of hyperpolarized ¹²⁹Xe 350 and a pressure source 375. Inoperation, a constant or variable pressure forces the hyperpolarized¹²⁹Xe to flow through the injector head 300 and out of the orifices 310to form a gaseous dispersion at a point proximate the entry site of thesubject. The constant or variable pressure can be generated with apressure sufficient to provide a gas flow rate sufficient to create thedesired bubble size. Typical flow rates are as described above, such asabout 3 cc/s or less (which in certain embodiments administers the gasdose of about 60 cc's over a 20 second injection period). The variablepressure can be provided to generate a pulsatile flow (either via a stepfunction operation or a ramped or gradual variation (increase and/ordecrease) over time). The pressure source 375 may be a power injectordevice, such as those which are well known to those of skill in the art.In operation, a rapid, controlled (pressure and volume) injection ofgaseous hyperpolarized ¹²⁹Xe can be administered to the subject.

The injector head 300 can be formed into a conduit disposed between the(intravenous or intrarterial) catheter which is configured to pierce theskin of the subject or may be positioned or formed in the catheteritself as noted above.

In certain embodiments, the temperature of the hyperpolarized gas can beadjusted (heated or cooled) prior to ejection through the injector head300. If cooled, the temperature should be sufficient to assure that thegas remains in the gaseous state at injection. In certain embodiments,the hyperpolarized xenon gas can be heated so that it is at least 70degrees F., and preferably in the range of about 98.6-105 degrees F., asit travels through the injector head orifices 310. The hyperpolarizedgas can be heated by exposing the captured gas to an elevatedtemperature as it travels along the flow path or by pre-heating acontainer holding the supply of ¹²⁹Xe prior to releasing thehyperpolarized gas into the administration exit flow path.Alternatively, or additionally, the injector head 300 may also beheated. In certain embodiments, heating methods and devices are selectedso that, in operation, they do not substantially negatively impact thepolarization of the gas (a liquid heated immersion bath for the ¹²⁹Xesource container or a supplemental heating container positioned in theflow path, solar or light energy directed to the polarized gas, aflowable heated gas which is directed over the outer surface of theenclosed gas flow path, etc).

As shown in FIGS. 8G and 8H, the injector head 300 can be configuredwith a convergent nozzle configuration. FIG. 8G illustrates that theinjector head 300 itself can have a convergent nozzle profile 301 todirect the gas from the flow path upstream thereof and into to theenclosed nozzle region and out of the orifices 310 positioned at theconvergent end thereof. FIG. 8H illustrates that the orifices 310 can beconfigured in the injector head 300 so that the individual orifices eachdefine a convergent nozzle, identified as a convergent nozzle orifice310 cn (decreases in area from the proximal end to the distal end alongthe axial direction of flow). Of course the injector head 300 mayincorporate both features, convergent nozzle orifices 310 cn with aconvergent profile 301.

FIG. 8I illustrates that the injector head 300 may include constant areaorifices 310 ca as well as convergent area nozzle orifices 310 cn. Inother embodiments, the injector head 300 may be configured with aconstant area body and/or the orifices 310 may be formed as onlyconstant area orifices 310 ca without convergent area nozzle orifices310 cn (not shown).

FIG. 8G illustrates that the administration can be performed such thatan additive can be mixed in situ with the polarized ¹²⁹Xe to help formthe fine dispersion formulation at ejection from the injector head 300.The additive is a pharmaceutical grade biocompatible substance which issubstantially non-depolarizing to the polarized ¹²⁹Xe gas. Examples ofsuitable substances may include blood, plasma, lipids, gases such as CO₂or noble gases including non-hyperpolarized xenon, deuteratedsubstances, or commercially available biomedical contrast agents. Seee.g., 60/014,321 and WO 97/37239 to Pines et al. and WO 99/52428 toJohnson et al., the contents of which are hereby incorporated byreference as if recited in full herein.

In certain embodiments, as shown in FIG. 8F, the additive can be anemulsifier which is added to a mixing chamber 375 positioned upstream ofthe injector head 300 so that the emulsifier is mixed with thehyperpolarized gas to form an emulsified composition of gas as it isextruded or travels through the orifices 310 of the injector head 300.The emulsifer material can be selected such that it is flowable and isable to encapsulate the hyperpolarized gas to promote surfacestabilization or to promote the fine dispersion of hyperpolarized gasinto the blood. As shown in FIG. 8F, the catheter or conduit 340 can beconfigured with two separate flow channels 353, 354, which end into theenclosed mixing chamber 375 upstream of the injector head 300. Themixing chamber 375 may include baffles, a venturi, or other mixercomponents to promote the intermixing of the hyperpolarized gas with theemulsifier (or other additive).

As shown in FIG. 8E, the hyperpolarized gas flow path 353 as well as theadditive flow path 354, may include a flow meter 355,455, respectively,or other flow or volume measurement device. In certain embodiments, theadditive is controlled so that a substantially lesser amount of additiveis used in comparison to the hyperpolarized gas (i.e., 25-40% less thanthe volume of gaseous polarized ¹²⁹Xe). It is noted that the injectionsystem and components described herein may also be suitable fordispensing other gases or agents such as hyperpolarized ³He.

The gas contacting surfaces of the injector head 300 can be formed of orcoated with suitable materials to inhibit the depolarization of the gasas it travels therethrough. Examples of suitable materials include, butare not limited to, alumminosilicate glass, certain polymer materials ormetallic materials or other materials as described herein. Surfacecoatings, such as a sputter coating of a non-depolarizing material ofhigh purity silver or aluminum. The relaxivity of high purity aluminumfor ¹²⁹Xe has been recently measured to be about 0.00225 cm/min. Metalsother than aluminum which can be used include indium, gold, zinc, tin,copper, bismuth, silver, niobium, and oxides thereof. Preferably, “highpurity” metals are employed (i.e., metals which are substantially freeof paramagnetic or ferrous impurities) because even minute amounts ofundesirable materials or contaminants may degrade the surface.Preferably, the metal is chosen such that it is well below 1 ppm inferrous or paramagnetic impurity content.

As noted above, because paramagnetic oxygen can be destructive to thepolarization of the polarized gas, it is preferred that any syringe,dose bags or other gas containers or gas contacting components such asconduit, catheters, injector heads, mixing chambers, and the like, bepreconditioned, i.e., carefully cleaned of magnetic impurities andpurged of paramagnetic oxygen. That is, any gas contacting containers orsurfaces are processed to reduce or remove the paramagnetic gases suchas oxygen from within the chamber and container walls.

It is preferred that the containers be prepared as briefly discussedabove. For containers made with rigid substrates, such as Pyrex®, UHVvacuum pumps can be connected to the container to extract the oxygen.However, a roughing pump can also be used which is typically cheaper andeasier than the UHV vacuum pump based process for both resilient andnon-resilient containers. Preferably, for resilient dose bags, the bagsare processed with several purge/pump cycles, e.g., pumping at or below20 mtorr for one minute, and then directing clean buffer gas (such asCO₂) into the container at a pressure of about one atm or until the bagis substantially inflated. The oxygen partial pressure is then reducedin the container. This can be done with a vacuum but it is preferredthat it be done with CO₂ (at least for the injection containers). Oncethe oxygen realizes the partial pressure imbalance across the containerwalls, it will outgas to re-establish equilibrium. Stated differently,the oxygen in the container walls is outgassed by decreasing the partialpressure inside the container chamber. Typical oxygen solubilities areon the order of 0.01-0.05; thus, 95-99% of the oxygen trapped in thewalls will convert to a gas phase. Prior to use or filling, thecontainer is evacuated, thus harmlessly removing the gaseous oxygen.Unlike conventional rigid containers, polymer bag containers cancontinue to outgas (trapped gases can migrate to the chamber because ofpressure differentials between the outer surface and the inner surface)even after the initial purge and pump cycles. Thus, care should be takento reduce this behavior especially when the final filling is nottemporally performed near the preconditioning of the container.Preferably, for bags or resilient containers, a quantity of clean fillergas is directed into the bag (to substantially equalize the pressurebetween the chamber and ambient conditions) and sealed for storage inorder to reduce the amount of further outgassing that may occur when thebag is stored and exposed to ambient conditions. This shouldsubstantially stabilize or decrease any further outgassing of thepolymer or container wall materials. In any event, the filler gas ispreferably removed (evacuated) prior to final filling with thehyperpolarized gas.

It is also preferred that the container, syringe, conduit, catheter,injector device, dose bag, or the like, be sterilized prior tointroducing the hyperpolarized product therein. As used herein the term“sterilized” includes cleaning containers and contact surfaces such thatthe container is sufficiently clean to inhibit contamination of theproduct such that it is suitable for medical and medicinal purposes. Inthis way, the sterilized container allows for a substantially sterileand non-toxic hyperpolarized product to be delivered for in vivointroduction into the patient. Suitable sterilization and cleaningmethods are well known to those of skill in the art.

The injectable dose is configured as a smaller quantity gas phaseproduct than the inhalation dose as described above. The inhalation dosecan be mixed with other inert gases such as nitrogen or otherbiocompatible fluids to help disperse or atomize the gas in the body(typically in the blood stream). As described above, subsequent toinhalation, at least a portion of the inhaled polarized gas enters intoa dissolved state which enters the pulmonary arterial vasculature,including the boundary tissue, cells, membranes, and pulmonary bloodvessels. Thus, a substantial amount of the dissolved polarized ¹²⁹Xeultimately enters the blood stream with an associated perfusion rate andcycles to the left atrium via the pulmonary vein, then to the leftventricle and out through the aorta.

Dissolved phase ¹²⁹Xe can have a relatively short relaxation time, T₁,generally thought to be due to the presence of oxygen and due toparamagnetic deoxyhemoglobin in the blood compared to ¹²⁹Xe whichremains in the gaseous phase in the blood. In addition, even within asubject's own circulatory system different T₁'s will be exhibited. Forexample, T₁ for substantially fully oxygenated human cell membranes (thesystemic arterial portion) will have a longer T₁ than the systemicvenous portion. That is, the T₁ of the polarized gas in the systemicvenous portion will be less than the T₁ of the polarized gas in thesystemic artery portion of the circulatory system which is moreoxygenated than the systemic venous portion.

As is also known to those of skill in the art, the polarized ¹²⁹Xe alsohas an associated transverse relaxation time, T₂*. In the bloodstream,the non-dissolved as well as the dissolved phase can have associated T₂*which is acceptable to obtain signal or images. Indeed, the ¹²⁹Xeremaining as a gas in human blood will tend to exhibit longer T₂*'s thanthat dissolved in human blood. Taking advantage of this characteristic,particularly for gas-phase based imaging (especially for T₂*'s which aregreater than at least about 30 milliseconds), multi-echo acquisitionmethods may be used. As will be appreciated by those of skill in theart, examples of suitable multi-echo methods include Echo Planar Imaging(“EP”), Rapid Acquisition with Relaxation Enhancement (“RARE”), FSE(“Fast Spin Echo”), Gradient Recalled Echoes (“GRE”), and BEST. Examplesof some suitable pulse sequences can be found in an article by John P.Mugler, III, entitled Gradient-Echo MR Imaging, RSNA Categorical Coursein Physics: The Basic Physics of MR Imaging, 1997; 71-88. For example,the article illustrates an example of a standard single RF spin-echopulse sequence with a 90 degree excitation pulse and a 180 degreerefocusing pulse. G_(P) is a phase-encoded gradient, G_(R) is thereadout gradient, G_(S) is the section-select gradient, and RF is theradio frequency. The article also illustrates a Gradient Recalled Echopulse sequence (GRE) with a flip angle α and a Rapid Acquisition withRelaxation Enhancement (RARE) pulse sequence as well as a single shotEcho Planar Imaging (EPI) pulse sequence with gradient recalled echoes.

FIG. 9 is a graph of one potential timing sequence which may be used andshows the delivery time of the injected gas (t_(inj)) and a MRI pulseimaging sequence according to one embodiment of the present invention.The imaging sequence illustrates a relatively long injection time duringwhich a plurality of short small flip angle (below about 45 degrees, andmore preferably below about 20 degrees) excitation pulses are directedat the target region. The exciation pulses begin shortly after the startof the injection (t−t₁) and end shortly after the injection ends(t_(end image)). In any case, the end of clinically useful signalgeneration associated with the injected hyperpolarized gas which issuitable for imaging is typically about 25 seconds after the gasinjection has ended, as the polarization of the gas has effectivelydecayed by this time. Of course, the choice of which flip angle andimaging procedure to use can depend on how many echoes can be done andhow many phase encodes steps are pursued. For single echo acquisitionsand increased (or optimal) SNR, having 128 phase encodes, a flip angleof about 5.1 degrees can be used.

It will be appreciated that at high magnetic field strength, it ispossible to obtain increased image signal strength based on thedissolved phase direct injection polarized gas as well as the signalstrength from gas phase ventilation in the lung. This can provideimproved signal image resolution associated with the injected gas. Itwill also be appreciated that there will be separate and distinctlyresolvable excitation resonances associated with the (dissolved) versusventilation (gas) imaging data signals. In contrast, at low magneticfield strengths, the separate resonances distinct at high fields, mayoverlap to provide an apparent increased image signal strengthassociated with both the dissolved and gas phase polarization.

Preferably, particularly for longer injection times (a deliveryadministered over a time which is greater than about 2.5 seconds), oneor more small flip angle pulses can be employed to excite the polarizedgas in the target region (such as the vasculature) to selectivelydestroy the polarization in a more localized image acquisition. As usedherein, the term “small angle” means less than about 45 degrees.

Preferably, the gas injection sized quantities of hyperpolarized ¹²⁹Xeare formulated as istopically enriched polarization gaseous products.

Examples

FIGS. 10A-10P are graphs of NMR spectra obtained about every 0.5 secondswith a 20 degree excitation pulse via a whole body imager based on abouta 3 cc polarized ¹²⁹Xe gas injection into the vein of a rabbit (total ofelapsed time from FIGS. 10A to 10P being about 8 seconds). The rabbitsurvived the experiment. The graphs illustrate that the gas remainedsubstantially in the gas phase (substantially non-dissolved or insolublein the bloodstream as it traveled through the bloodstream during theimage acquisition). The signal strength at 8 seconds (FIG. 10P) beingabout 0.65 that of the original signal (FIG. 10A). The rabbit was placedin a whole body imager so that the exact location of the signal withinthe rabbit's body is not disclosed in the spectra. It is noted that alarge quantity of the injected gas remained in the gas phase uponinjection, most likely due to the size of the lumen used, about 0.5 mm.

It is also notable that the T₁ of the gas in the blood is relativelylong, at least about 20 seconds (for comparison, the T₁ of gas dissolvedin blood is typically less than 20 seconds, such as about 4-6 secondsdepending on oxygenation).

In summary, it is anticipated that diagnostic images can be obtainedaccording to the present invention for desired target organs or systems,such as but not limited to, the kidneys, the brain or cranium region forcerebral assessment (grey/white matter/blood), the liver, spleen,intestines, lower extremity blood circulation, tumor assessment (oxygentension) and coronary artery restrictions/blood flow and other regionsof interest.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. In the claims, means-plus-function clauses are intended tocover the structures described herein as performing the recited functionand not only structural equivalents but also equivalent structures.Therefore, it is to be understood that the foregoing is illustrative ofthe present invention and is not to be construed as limited to thespecific embodiments disclosed, and that modifications to the disclosedembodiments, as well as other embodiments, are intended to be includedwithin the scope of the appended claims. The invention is defined by thefollowing claims, with equivalents of the claims to be included therein.

1-63. (canceled)
 64. A method of evaluating the efficacy of targeteddrug therapy, comprising the steps of: delivering a quantity ofpredetermined gene treatment preparation or pharmaceutical drug in vivointo a mammalian subject having a target site and a treatment condition;injecting a predetermined quantity of gaseous phase hyperpolarized ¹²⁹Xein vivo into a mammalian subject such that the hyperpolarized gas isdelivered to the target site in gaseous or dissolved form; generating aNMR image or spectroscopic signal of the target site associated with theinjected hyperpolarized ¹²⁹Xe gas; and evaluating the NMR image orspectroscopic signal to evaluate the efficacy of the gene treatment ordrug on the treatment condition administered in said delivering step.65. A method according to claim 64, further comprising the step ofacquiring at least two sets of data, the data representing twotemporally spaced apart points in time, to evaluate if the treatmentcondition is influenced by the drug or gene therapy introduced in saiddelivering step.
 66. A method according to claim 64, further comprisingthe step of evaluating whether the drug is properly delivered to thetarget site.
 67. A method according to claim 64, wherein said at leasttwo data sets correspond with a hyperpolarized 129Xe gas NMR signal dataacquisition obtained both before said delivering step and after saiddelivering step.
 68. A method according to claim 65, further comprisingat least one of adjusting the quantity or formulation of the drug andconfirming the proper delivery to the target site.
 69. A methodaccording to claim 64, wherein the treatment condition is one of cancer,cardiac, renal, hepatic or pulmonary function, and cerebral function,and wherein the target site is selected so as to administer polarized¹²⁹Xe gas to a region representative of that condition. 70-79.(canceled)
 80. A method of preparing a gas container having a sealablegas holding chamber prior to the introduction of a polarized producttherein, comprising the steps of: (a) evacuating the gas container; (b)introducing a quantity of CO₂ gas therein; and (c) repeating step (a)after step (b). 81-88. (canceled)